Piperidine derivatives useful as modulators of chemokine receptor activity

ABSTRACT

The invention provides a compound of formula (I), wherein: T is C(O) or S(O) 2 ; W is C(O) or S(O) 2 ; X is CH 2 , O or NH; Y is CR 5  or N; R 1  is optionally substituted aryl or optionally substituted heterocyclyl; R 2  is hydrogen or C 1-6 alkyl; R 3  is hydrogen or optionally substituted C 1-6 alkyl; and R 4  is alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heterocyclyl; that are modulators of chemokine (especially CCR3) activity and are especially useful for treating asthma and/or rhinitis

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national phase application under 35 U.S.C. § 371of PCT International Application No. PCT/SE02/01311, which has anInternational filing date of Jul. 1, 2002, and which designated UnitedKingdom Application Serial No. 0116179.3, filed Jul. 2, 2001, and UnitedKingdom application Ser. No. 0123037.4, filed Sep. 25, 2001, as priorityapplications. The contents of all these applications are incorporated byreference in their entirety.

The present invention concerns piperidine derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed inWO99/38514, WO99/04794 and WO00/35877.

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation and also play a rôle in thematuration of cells of the immune system. Chemokines play an importantrôle in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif. The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C-X-C, or α) andCys-Cys (C-C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β.

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formedfrom histidine by histidine decarboxylase. It is found in most tissuesof the body, but is present in high concentrations in the lung, skin andin the gastrointestinal tract. At the cellular level inflammatory cellssuch as mast cells and basophils store large amounts of histamine. It isrecognised that the degranulation of mast cells and basophils and thesubsequent release of histamine is a fundamental mechanism responsiblefor the clinical manifestation of an allergic process. Histamineproduces its actions by an effect on specific histamine G-proteincoupled receptors, which are of three main types, H1, H2 and H3.Histamine H1 antagonists comprise the largest class of medications usedin the treatment of patients with allergic disorders, especiallyrhinitis and urticaria. Antagonists of H1 are useful in controlling theallergic response by for example blocking the action of histamine onpost-capillary venule smooth muscle, resulting in decreased vascularpermeability, exudation and oedema. The antagonists also produceblockade of the actions of histamine on the H1 receptors on c-typenociceptive nerve fibres, resulting in decreased itching and sneezing.

Viral infections are known to cause lung inflammation. It has been shownexperimentally that the common cold increases mucosal output of eotaxinin the airways. Instillation of eotaxin into the nose can mimic some ofthe signs and symptoms of a common cold. (See, Greiff L et al Allergy(1999) 54(11) 1204-8 [Experimental common cold increase mucosal outputof eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch.Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normalairway epithelial cells after virus A infection].)

The present invention provides a compound of formula (I):

wherein:

-   T is C(O) or S(O)₂;-   W is C(O) or S(O)₂;-   X is CH₂, O or NH;-   Y is CR⁵ or N;-   R¹ is optionally substituted aryl or optionally substituted    heterocyclyl;-   R² is hydrogen or C₁₋₆ alkyl;-   R³ is hydrogen or optionally substituted C₁₋₆ alkyl;-   R⁴ is alkyl, cycloalkyl, optionally substituted aryl, optionally    substituted aralkyl or optionally substituted heterocyclyl;-   R⁵ is hydrogen or C₁₋₆ alkyl;-   wherein the foregoing aryl and heterocyclyl moieties are optionally    substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)_(p)R²⁵,    OC(O)NR⁶R⁷, NR⁸R⁹, NR¹⁰C(O)R¹¹, NR¹²C(O)NR¹³R¹⁴, S(O)₂NR¹⁵R¹⁶,    NR¹⁷S(O)₂R¹⁸, C(O)NR¹⁹R²⁰, C(O)R²¹, CO₂R²², NR²³CO₂R²⁴, C₁₋₆ alkyl,    CF₃, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, OCF₃, C₁₋₆    alkoxy(C₁₋₆)alkoxy (preferably not forming an acetal), C₁₋₆    alkylthio, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itself    optionally substituted by C₁₋₄ alkyl or oxo), methylenedioxy,    difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy,    phenylthio, phenyl(C₁₋₄)alkoxy, heteroaryl, heteroaryl(C₁₋₄)alkyl,    heteroaryloxy or heteroaryl(C₁₋₄)alkoxy; wherein any of the    immediately foregoing phenyl and heteroaryl moieties are optionally    substituted with halogen, hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl),    S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄    alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄    alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃;-   p and q are, independently, 0, 1 or 2;-   R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,    R²¹, R²², and R²³ are, independently, hydrogen, C₁₋₆ alkyl    (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),    CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,    hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄    alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano,    C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄    alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl),    CF₃ or OCF₃) or heterocyclyl (itself optionally substituted by    halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,    S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),    C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),    NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);-   alternatively NR⁶R⁷, NR⁸R⁹, NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁹R²⁰ or N(C₁₋₄    alkyl)₂ may, independently, form a 4-7 membered heterocyclic ring,    azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or    1,4-piperazine, the latter optionally substituted by C₁₋₄alkyl on    the distal nitrogen;-   R²⁵, R¹⁸ and R²⁴ are, independently, C₁₋₆ alkyl (optionally    substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆    alkenyl), phenyl (itself optionally substituted by halogen, hydroxy,    nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups    may join to form a ring as described for R⁶ and R⁷ above),    S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂ (and these alkyl groups may join to form a ring as described    for R⁶ and R⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,    C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R⁶ and R⁷ above), CO₂H,    CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄    alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionally substituted    by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R⁶ and    R⁷ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring    as described for R⁶ and R⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl    groups may join to form a ring as described for R⁶ and R⁷ above),    CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),    C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);-   or an N-oxide thereof; or a pharmaceutically acceptable salt    thereof; or a solvate thereof.

Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride,dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate orp-toluenesulfonate. Salts also include metal salts, such as alkali metalsalts (for example a sodium salt).

The compounds of the invention may exist as solvates (such as hydrates)and the present invention covers all such solvates.

Halogen includes fluorine, chlorine, bromine and iodine.

Alkyl groups and moieties (including those of alkoxy) are straight orbranched chain and are, for example, methyl, ethyl, n-propyl,1-methylethyl or 1,1-dimethylethyl.

Alkenyl is, for example, vinyl or allyl.

Alkynyl is, for example, propargyl.

Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl,cyclopentyl, cyclohexyl, norbornyl or camphoryl. The cycloalkyl ring isoptionally fused to a benzene ring (for example forming abicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).

Haloalkyl is preferably CF₃. Haloalkoxy is preferably OCF₃.

Aryl is preferably phenyl or naphthyl.

Arylalkyl is preferably aryl(C₁₋₄ alkyl) for example benzyl or2-phenyleth-1-yl.

Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring,optionally fused to one or more other rings, comprising at least oneheteroatom selected from the group comprising nitrogen, oxygen andsulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl),pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for examplein 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl,2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl),benz[b]thienyl (also known as benzthienyl or benzthiophenyl),2,3-dihydrobenz[b]thienyl (for example in1,1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl,benztriazolyl, benzoxazolyl, benzthiazolyl (for example in1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, animidazopyridinyl (such as imidazo[1,2a]pyridinyl),thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known asbenzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (alsoknown as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl(for example in a coumarinyl or a chromonyl),3,4-dihydro-1H-2,1-benzothiazinyl (for example in2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (forexample 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (forexample in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example[1,6]naphthyridinyl or [1,8]naphthyridinyl or in1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl ordibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof(such as a pyridine N-oxide), or an S-oxide or S-dioxide thereof.

An N-oxide of a compound of formula (I) is, for example, a1-oxido-[1,4′]bipiperidinyl-1′-yl compound.

In one particular aspect the present invention provides a compound offormula (I) wherein: T is C(O) or S(O)₂; W is C(O) or S(O)₂; X is CH₂, Oor NH; Y is CR⁵ or N; R¹ is optionally substituted aryl or optionallysubstituted heterocyclyl; R² is hydrogen or C₁₋₆ alkyl; R³ is hydrogenor optionally substituted C₁alkyl; R⁴ is alkyl; optionally substitutedaryl, optionally substituted aralkyl or optionally substitutedheterocyclyl; R⁵ is hydrogen or C₁₋₆ alkyl; wherein the foregoing aryland heterocyclyl moieties are optionally substituted by: halogen, cyano,nitro, hydroxy, oxo, S(O)_(p)R²⁵, OC(O)NR⁶R⁷, NR⁸R⁹, NR¹⁰OC(O)R¹¹,NR¹²C(O)NR¹³R¹⁴, S(O)₂NR¹⁵R¹⁶, NR¹⁷S(O)₂R¹⁸, C(O)NR¹⁹R²⁰, C(O)R²¹,CO₂R²², NR²³CO₂R²⁴, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy(C₁)alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆ alkylthio,C₁₋₆ haloalkylthio, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itselfoptionally substituted by C₁₋₄ alkyl or oxo), methylenedioxy,difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy, phenylthio,phenyl(C₁₋₄)alkoxy, heteroaryl, heteroaryl(C₁₋₄)alkyl, heteroaryloxy orheteroaryl(C₁₋₄)alkoxy; wherein any of the immediately foregoing phenyland heteroaryl moieties are optionally substituted with halogen,hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; p and q are,independently, 0, 1 or 2; R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹R²⁰, R²¹, R²², and R²³ are, independently,hydrogen, C₁₋₆ alkyl (optionally substituted by halogen, hydroxy orC₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl), phenyl (itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), NH(C₁₋₄alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl(itself optionally substituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);alternatively NR⁶R⁷, NR⁸R⁹, NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁹R²⁰, may,independently, form a 4-7 membered heterocyclic ring, azetidine,pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, thelatter optionally substituted by C₁₋₄alkyl on the distal nitrogen; R²⁵,R¹⁸ and R²⁴ are, independently, C₁₋₆ alkyl (optionally substituted byhalogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl), phenyl (itselfoptionally substituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups mayjoin to form a ring as described for R⁶ and R⁷ above), cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (andthese alkyl groups may join to form a ring as described for R⁶ and R⁷above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂ (and these alkyl groups may join to form a ring as described forR⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R⁶ and R⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may jointo form a ring as described for R⁶ and R⁷ above), CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);or an N-oxide thereof; or a pharmaceutically acceptable salt thereof;

or a solvate thereof.

In a further aspect X is O.

In another aspect R¹ is phenyl substituted with one or more of fluorine,chlorine, C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especiallymethoxy).

In a further aspect R¹ is phenyl optionally substituted (for examplewith one, two or three of) by halogen (especially fluoro or chloro),C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy). In astill further aspect R¹ is phenyl substituted by one, two or three of:fluoro, chloro, methyl or methoxy. In another aspect R¹ is phenyloptionally substituted by halogen (especially fluoro or chloro), C₁₋₄alkyl (especially methyl); especially optionally substituted (forexample independently with one, two or three of, especially two or threeof) by fluoro, chloro or methyl. In a still further aspect R¹ is3,4-dichlorophenyl, or, additionally 2-chloro-4-fluorophenyl,2-methyl-4-chlorophenyl, 2,4-dichloro-3-methylphenyl or3,4-dichloro-2-methylphenyl.

In another aspect one of T and W is C(O) and the other is S(O)₂.

In a still further aspect T is C(O).

In another aspect W is S(O)₂.

In yet another aspect of the invention, and when Y is CR⁵, the compoundsof formula (I) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the T-N(R³)-W—R⁴ groupare both equatorial on the cyclohexane ring.

In a still further aspect of the invention Y is CH or N; especially N.

In yet another aspect R² is hydrogen or methyl; for example R² ishydrogen.

In a further aspect R³ is hydrogen or methyl; for example hydrogen.

In a still further aspect R⁴ is unsubstituted phenyl, mono-substitutedphenyl, unsubstituted heterocyclyl or mono-substituted heterocyclyl, thesubstituents being chosen from those described above.

In a further aspect the present inention provides a compound of formula(I) wherein R⁴ is aryl (for example phenyl or naphthyl; especiallyphenyl) optionally substituted by one or more of C₁₋₆ alkyl (for examplemethyl or ethyl), C₁₋₄ alkoxy (for example methoxy), halogen (forexample chloro or fluoro), CF₃, CN, CO₂(C₁₋₄ alkyl) (for exampleCO₂CH₃), OH, OCF₃, S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃) or NR⁸R⁹(wherein R⁸ and R⁹ are, independently, hydrogen or C₁₋₄ alkyl); orheterocyclyl (for example imidazolyl, thienyl, tetrahydrothienyl,thiazolyl, 1,3,4-thiadiazolyl, pyridyl or dihydroisoquinolinyl)optionally substituted by oxo, halogen (for example chloro or fluoro),C₁₋₄ alkyl (for example methyl), NR⁸R⁹ (wherein R⁸ and R⁹ are,independently, hydrogen or C₁₋₄ alkyl), piperidinyl or morpholinyl. Inanother aspect R⁴ is phenyl optionally substituted by one or more ofC₁₋₆ alkyl (for example methyl or ethyl), C₁₋₄ alkoxy (for examplemethoxy), halogen (for example chloro or fluoro), CF₃, CN, CO₂(C₁₋₄allyl) (for example CO₂CH₃), OH, OCF₃, S(O)₂(C₁₋₄ alkyl) (for exampleS(O)₂CH₃) or NR⁸R⁹ (wherein R⁸ and R⁹ are, independently, hydrogen orC₁₋₄ alkyl).

In a further aspect of the invention R⁴ is substituted (especiallymono-substituted) phenyl, the substituents being chosen from thosedescribed above.

In a still further aspect R⁴ is phenyl or heterocyclyl, either of whichis optionally substituted by: halo, hydroxy, nitro, cyano, oxo, amino,C₁₋₄ alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl),S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein k is 0, 1 or 2(preferably 2); and R²⁶ is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl), C₁₋₄haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

In yet another aspect R⁴ is phenyl or heterocyclyl, either of which isoptionally substituted by: halo, hydroxy, nitro, cyano, oxo, NR⁸R⁹(wherein R⁸ and R⁹ are, independently, hydrogen or C₁₋₄ alkyl), C₁₋₄alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl),C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein k is 0, 1 or 2 (preferably 2); and R²⁶is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such ascyclopropylmethyl) or phenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

In one aspect the variable R⁴ is phenyl optionally substituted by: halo,hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itself optionally substitutedby S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein kis 0, 1 or 2 (preferably 2); and R²⁶ is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl,C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl), C₁₋₄haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl) or S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form aring as described for R⁶ and R⁷ above).

In another aspect the variable R⁴ is phenyl optionally substituted by:halo, hydroxy, nitro, cyano, NR⁸R⁹ (wherein R⁸ and R⁹ are,independently, hydrogen or C₁₋₆ alkyl), C₁₋₄ alkyl (itself optionallysubstituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶(wherein k is 0, 1 or 2 (preferably 2); and R²⁶ is C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) orphenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups mayjoin to form a ring as described for R⁶ and R⁷ above).

In another aspect the variable R⁴ is phenyl optionally substituted by:halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itself optionallysubstituted by S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein k is 0, 1or 2; and R²⁶ is C₁₋₄ alkyl or phenyl) or C₁₋₄ haloalkylthio.

In a further aspect the variable R⁴ is phenyl optionally substituted by:halo, hydroxy, nitro, cyano, NR⁸R⁹ (wherein R⁸ and R⁹ are,independently, hydrogen or C₁₋₄ alkyl), C₁₋₄ alkyl (itself optionallysubstituted by S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein k is 0, 1or 2; and R²⁶ is C₁₋₄ alkyl or phenyl) or C₁₋₄ haloalkylthio.

The amine group NR⁸R⁹ is, for example, mono-(C₁₋₄) alkylamino (such asNHCH₃ or NHCH₂CH₃) or di-(C₁₋₄) alkylamino (such as N(CH₃)₂).

In yet another aspect of the invention R⁴ is phenyl mono-substitutedwith halogen (for example fluorine or chlorine), C₁₋₄ alkyl (for examplemethyl or ethyl), C₁₋₄ alkoxy (for example methoxy or ethoxy) or NR⁸R⁹(wherein R⁸ and R⁹ are, independently, hydrogen or C₁₋₆ alkyl; and NR⁸R⁹is especially NHCH₃, NHCH₂CH₃ or N(CH₃)₂).

In a further aspect R⁴ is phenyl substituted with halogen, alkyl oralkoxy.

In a still further aspect of the invention R⁴ is phenyl mono-substitutedwith halogen (especially chlorine) or C₁₋₄ alkyl (especially methyl).

In yet another aspect R⁵ is hydrogen.

In another aspect the present invention provides a pharmaceuticallyacceptable salt of a compound of formula (I), for example a metal salt{such as an alkali metal salt (for example the sodium salt)} of acompound of formula (I).

Compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih)are examples of compounds of formula (I).

In a still further aspect the present invention provides a compound offormula (Ia):

wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

In a still further aspect the present invention provides a compound offormula (Ib):

wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

In a still further aspect the present invention provides a compound offormula (Ic):

wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (Ic) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the C(O)N(R³)S(O)₂R⁴group are both equatorial on the cyclohexane ring.

In a still further aspect the present invention provides a compound offormula (Id):

wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

In a still further aspect the present invention provides a compound offormula (Ie):

wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

In a still further aspect the present invention provides a compound offormula (If):

wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (If) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the S(O)₂N(R³)C(O)R⁴group are both equatorial on the cyclohexane ring.

In a still further aspect the present invention provides a compound offormula (Ig):

wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (Ig) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the C(O)N(R³)C(O)R⁴group are both equatorial on the cyclohexane ring.

In a still further aspect the present invention provides a compound offormula (Ih):

wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (Ih) are preferably trans in terms of relativestereochemistry, that is the piperidine ring and the S(O)₂N(R³)S(O)₂R⁴group are both equatorial on the cyclohexane ring.

A compound of formula (Ia) is, for example:

-   N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;-   N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   4-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   2-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;-   N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   4-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   2-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;-   N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   2-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;-   N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   2-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;-   N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   4-Chloro-N-[[(4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   2-Chloro-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-3-trifluoromethyl-benzenesulfonamide;-   3-Cyano-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenemethanesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-methanesulfonamide;-   N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   4-Chloro-N-[[4-(4-chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-N,4-dimethyl-benzenesulfonamide;-   N-[[4-[(3,4-Dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   4-Chloro-N-[[4-[(3,4-dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-[(3,4-Dichlorophenyl)amino][1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   3-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   3,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   3-Cyano-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethoxy-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)([1,4′-bipiperidin]-1′-yl]carbonyl)-3,4-dimethoxy-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(3,3-dimethyl-2-oxo-1-azetidinyl)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-hydroxy-benzenesulfonamide;-   N-[(4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(trifluoromethyl)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoic    acid, methyl ester;-   2-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[5-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-1,3,4-thiadiazol-2-yl]-acetamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-(dimethylamino)-1-naphthalenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-naphthalenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-dimethyl-5-thiazolesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(1-piperidinyl)-3-pyridinesulfonamide;-   5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   5-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]tetrahydro-3-thiophenesulfonamide;    1,1-dioxide-   4,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethyl-benzenesulfonamide;-   4-n-Butyl-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   2,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-thiophenesulfonamide;-   4-n-Butoxy-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1-methyl-1H-imidazole-4-sulfonamide;-   5-Amino-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1,3,4-thiadiazole-2-sulfonamide;-   4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(4-morpholinyl)-3-pyridinesulfonamide;-   6-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-pyridinesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(1,1-dimethylethyl)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-methyl-2-pyridinesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;-   5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluoro-benzenesulfonamide;-   4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;-   3-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;-   N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;-   2-chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;-   2-chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;-   N-[[4    (2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]+methyl-benzenesulfonamide;-   N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide,-   2-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   2-chloro-N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   2-chloro-N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   2-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   2-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;-   4-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   2-chloro-N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   4-chloro-N-([4-(2,5-dichlorophenoxy)[1,4′-bipiperidin]-1′-ylcarbonyl]-benzenesulfonamide;-   5    N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   2-chloro-N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;-   N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;-   N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;-   N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methoxy-benzenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl)-2,5-difluoro-benzenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-(dimethylamino)-benzenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)(1,4′-bipiperidin]-1′-yl]carbonyl]-2-methoxy-benzenesulfonamide;-   4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   3,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   Methyl    2-[[[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoate;-   2-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;-   5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   4,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   4-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethyl-benzenesulfonamide;-   2,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-thiophenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;-   4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin)-1′-yl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;-   5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluoro-benzenesulfonamide;-   4-chloro-N-[[4-(3,4-dichlorophenoxy)([1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;-   3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;-   N-[[4-(3,4-dichlorophenoxy)(1,4′-bipiperidin]-1′-yl]carbonyl]-2,6-dimethyl-benzenesulfonamide;    or,-   N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide.

A compound of formula (Ib) is, for example:

-   4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(2-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-(3-cyanobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(4-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(2-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(2,4-dichloro-3-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(4-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(2-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(3-cyanobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-benzoyl-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-benzoyl-4-(2,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-[(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-[1,4′-bipiperidine]-1′-sulfonamide;-   N-(cyclohexylcarbonyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(2-methyl-1-oxopropyl)-[1,4′-bipiperidine)-1′-sulfonamide;-   4-(3,4-dichlorophenoxy)-N-(2-phenylacetyl)-[1,4′-bipiperidine]-1′-sulfonamide;    or,-   N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide.

A compound of formula (Ic) is, for example:

-   Trans    N-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-N,4-dimethyl-benzenesulfonamide;-   Trans    4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methyl-benzenesulfonamide;-   Trans    3-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    4-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    3,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    3-cyano-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-dimethoxy-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3,4-dimethoxy-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(3,3-dimethyl-2-oxo-1-azetidinyl)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-hydroxy-benzenesulfonamide;-   Trans    N-[(4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-(trifluoromethyl)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    2-[[[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]amino]-sulfonyl]-benzoic    acid, methyl ester;-   Trans    2-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    N-[5-[[[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]amino]sulfonyl]-1,3,4-thiadiazol-2-yl]-acetamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-(dimethylamino)-1-naphthalenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-naphthalenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4-dimethyl-5-thiazolesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(1-piperidinyl)-3-pyridinesulfonamide;-   Trans    5-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;-   Trans    5-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]tetrahydro-3-thiophenesulfonamide,    1,1-dioxide;-   Trans    4,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl-1-carbonyl)-2-thiophenesulfonamide;-   Trans    4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-dimethyl-benzenesulfonamide;-   Trans    4-n-butyl-N-([4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    2,5-dichloro-N-[(4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-thiophenesulfonamide;-   Trans    4-n-butoxy-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-1-methyl-1H-imidazole-4-sulfonamide;-   Trans    5-amino-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-1,3,4-thiadiazole-2-sulfonamide;-   Trans    4-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(4-morpholinyl)-3-pyridinesulfonamide;-   Trans    6-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-pyridinesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(1,1-dimethylethyl)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-methyl-2-pyridinesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-difluoro-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;-   Trans    5-chloro-N-[[4[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4-difluoro-benzenesulfonamide;-   Trans    4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-difluoro-benzenesulfonamide;-   Trans    3-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methyl-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methoxy-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,6-dimethyl-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;    or,-   Trans    N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(dimethylamino)-benzenesulfonamide.

A compound of formula (Id) is, for example:

-   4-(3,4-Dichlorophenoxy)-N-(2-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;-   4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;-   4-(3,4-Dichlorophenoxy)-N-(4-chlorobenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;-   4-(3,4-Dichlorophenoxy)-N-benzoyl-[1,4′-bipiperidine]-1′-carboxamide;-   4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide;    or,-   4-(3,4-dichlorophenoxy)-N-[[4-(1,1-dimethylethyl)phenyl)sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide.

A compound of formula (Ie) is, for example:

-   [4-(3,4-dichlorophenoxy)-N-(phenylsulfonyl)-1,4′-bipiperidine]-1′-sulfonamide.

A compound of formula (If) is, for example:

-   Trans    N-benzoyl-4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanesulfonamide.

A compound of formula (Ig) is, for example:

-   Trans    N-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzamide.

A compound of formula (Ih) is, for example:

-   Trans    N-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]sulfonyl]-benzenesulfonamide.

Compounds of formula (I) (for example compounds of formula (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig) or (Ih)) can be prepared by the methodsdescribed below.

A compound of formula (Ic), (If), (Ig) or (Ih) where R³ and R⁵ are bothhydrogen may be converted to a compound of formula (Ic), (If), (Ig) or(Ih) where R⁵ is alkyl and R³ is hydrogen by deprotonation to a dianion,for example with 2 equivalents of LDA, followed by reaction with analkylating agent, R⁵Hal (wherein Hal is, for example chlorine).

A compound of formula (Ic), (If), (Ig) or (Ih) where R⁵ is hydrogen andR³ is not hydrogen may be converted to a compound of formula (Ic), (If),(Ig) or (Ih) where R⁵ is alkyl and R³ is not hydrogen by deprotonation,for example with 1 equivalent of LDA, followed by reaction with analkylating agent, R⁵Hal.

A compound of formula (I), wherein R³ is not hydrogen, can be preparedby alkylating a compound of formula (I), wherein R³ is hydrogen, with asuitable alkylating agent (for example R³-L, wherein L is a leavinggroup such as triflate, a halide or a diazo group) in the presence of asuitable base (such as sodium hydride) in a suitable solvent.

A compound of formula (I), wherein R³ is hydrogen, T is C(O) and Y is N,can be prepared by reacting a compound of formula (II):

with an isocyanate of formula R⁴N═C═O in the presence of a suitablesolvent at a suitable temperature (such as room temperature).Isocyanates of formula R⁴WN═C═O are commercially available or can beprepared by optional adaptation of methods described in the literature.

A compound of formula (I), wherein T is C(O), W is S(O)₂ and Y is N, canbe prepared by reacting a compound of formula (II) with a compound offormula (XXII). A compound of formula (XXII):

may be prepared from a sulfonamide R⁴SO₂NHR³ and p-nitrophenylchloroformate in the presence of a base, for example triethylamine and acatalyst, for example DMAP, typically at room temperature.

A compound of formula (II) can be prepared by deprotecting a compound offormula (III):

for example using trifluoroacetic acid in a suitable solvent (such asdichloromethane) or using a source of hydrogen chloride in a suitablesolvent (such as dioxane).

A compound of formula (III), wherein R² is hydrogen, can be prepared byreacting a compound of formula (IV):

with a compound of formula (V):

in the presence of NaBH(OAc)₃ and acetic acid.

A compound of formula (E), wherein R² is C₁₋₆ alkyl, can be prepared byreacting a compound of formula (XVII):

with a Grignard reagent of formula R²MgHal (wherein Hal is chlorine,bromine or iodine) in a suitable solvent, such as tetrahydrofuran.

A compound of formula (XVII) can be prepared by reacting a compound offormula (IV) with a compound of formula (V) in the presence of titaniumtetrisopropoxide, for example in dichloroethane, followed by theaddition of diethylaluminium cyanide to a solution, for example intoluene.

A compound of formula (I), wherein R³ is hydrogen, T is S(O)₂, W is C(O)and Y is N, can be prepared by reacting a compound of formula (IX):

with a compound of formula (II) in the presence of a suitable base (suchas triethylamine) in a suitable solvent (such as tetrahydrofuran) at asuitable temperature (such as below −60° C.). A compound of formula (IX)can be prepared by reacting an acid R⁴CO₂H with ClS(O)₂N═C═O, forexample below 80° C.

Alternatively, a compound of formula (I), wherein R³ is hydrogen, T isS(O)₂, W is C(O) and Y is N, can be prepared by reacting a compound offormula (XVIII):

with an acyl halide R⁴COHal in the presence of a base, for exampletriethylamine in a suitable solvent, for example dichloromethane, forexample at room temperature.

A compound of formula (XVIII) may be prepared by the reaction of acompound of formula (II) with sulfamide, for example in dioxan atreflux.

A further method of preparing a compound of formula (I), wherein R³ ishydrogen, T is S(O)₂, W is C(O) and Y is N, is to react a compound offormula (XIX):

with an acyl halide R⁴COHal in the presence of a base, for exampletriethylamine in a suitable solvent, for example dichloromethane, forexample at room temperature, followed by deprotection of the carbamateso formed, for example with trifluoroacetic acid in dichloromethane.

A compound of formula (XIX) can be prepared from a compound of formula(II) and a compound of formula (XX):

in a suitable solvent for example dichloromethane typically at roomtemperature.

A compound of formula (I) wherein T and W are both S(O)₂ and Y is N, canbe prepared by reacting a compound of formula (X):

with a sulfonamide R⁴S(O)₂NHR³ in the presence of a base (such ascalcium oxide), in a suitable solvent (such as DMSO) at a temperaturepreferably in the range 50-110° C. (For example see DE 1618439; DE1249259; Chemical Abstracts 1967, 67, 116716a). A compound of formula(X) can be prepared by reacting a compound of formula (II) with S(O)₂Cl₂in the presence of a suitable base (such as triethylamine).

Alternatively, a compound of formula (I) wherein T and W are both S(O)₂and Y is N, can be prepared by reacting a compound of formula (XVIII)with a sulfonyl chloride R⁴SO₂Cl in the presence of a base, for exampletriethylamine, preferably with dimethylaminopyridine as catalyst in asuitable solvent, for example dichloromethane, for example at roomtemperature.

A compound of formula (I) wherein T is C(O), W is S(O)₂ and Y is CR⁵,can be prepared by firstly hydrolysing a compound of formula (XI):

wherein the ester is preferably a C₁₋₆ alkyl group, and reacting theproduct so formed with R⁴S(O)₂NHR³ in the presence of an appropriatecoupling agent (such as ethyl dimethylaminopropyl carbodiimide (EDCI),with 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBT)) ina suitable solvent, for example DMF.

A compound of formula (XI), wherein R² is hydrogen, can be prepared byreductively aminating a compound of formula (XI):

with a compound of formula (XIII):

A compound of formula (X) where R² is alkyl can be prepared by aminonitrile formation between compounds of formula (XII) and (XIII) followedby displacement of the nitrile with a grignard reagent.

A compound of formula (I), wherein T and W are both C(O) and Y is CH orN, can be prepared by heating a compound of formula (XIV):

in the presence of R⁴C(OR′)₂N(CH₃)₂ or R⁴C(OR′)₃, wherein R′ is methylor ethyl, or (OR′)₃ is (OCH₂)₃CCH₃. A compound of formula (XI) where Yis CR⁵ can be prepared by firstly hydrolysing a compound of formula (XI)and then coupling the product so formed with an amine R³NH₂ in thepresence of an appropriate coupling agent (such as ethyldimethylaminopropyl carbodiimide, with 4-dimethylaminopyridine or1-hydroxybenzotriazole) in a suitable solvent, for example DMF. Acompound of formula (XIV) where Y is N and R³ is H may be prepared byreaction of a compound of formula (II) with sodium cyanate in thepresence of an acid, for example acetic acid. A compound of formula(XIV) where Y is N and R³ is alkyl may be prepared by reaction of acompound of formula (II) with a compound of formula (XXI): R³—N═C═O; inan inert solvent, for example dichloromethane, for example at roomtemperature.

A compound of formula (I), wherein T is S(O)₂, W is C(O) and Y is CR⁵,can be prepared by coupling a compound of formula (XV):

to an acid R⁴CO₂H in the presence of an appropriate coupling agent (suchas ethyl dimethylaminopropyl carbodiimide, 4-dimethylaminopyridine orHOBT) in a suitable solvent.

A compound of formula (I), wherein T and W are both S(O)₂ and Y is CH,can be prepared by coupling a compound of formula (XV) to a sulfonylchloride R⁴S(O)₂CH, in the presence of a base and a solvent (such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran).

A compound of formula (XV) can be prepared by reductively aminating acompound of formula (XVI):

with a compound of formula (IV) to obtain a compound wherein R² ishydrogen, or aminonitrile formation followed by a Grignard reaction toobtain a compound wherein R² is alkyl.

A compound of formula (XVI) can be prepared by reacting

with CH₂═CR⁵—S(O)₂NHR³ at an elevated temperature (such as in refluxingtoluene) and then hydrolysing the silyl enol ether (such as with aceticacid).

A compound of formula (I) where Y is CR⁵ and R⁵ is not hydrogen may beprepared from a compound of formula (I) where Y is CH by reaction of thedianion (R³ is H) or monoanion (R³ is alkyl) (formed with a suitablebase, for example LDA) with an alkylating agent (for example R⁵-L,wherein L is a leaving group such as triflate or a halide) in a suitablesolvent for example THF for example at 0° or below.

Further compounds of formula (I) can be prepared by adaptation of: theroutes described above, methods described in the art or the Examplesrecited below. The intermediates identified above are commerciallyavailable or can be prepared by using or adapting methods described inthe art.

In another aspect the present invention provides processes for thepreparation of compounds of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)).

The intermediates of formula (X), (XI), (XIV), (XV), (XVI) and (XIX)defined herein are novel and these, and processes for their preparation,are provided as further features of the invention.

The compounds of the invention have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CCR3)activity, and may be used in the treatment of autoimmune, inflammatory,proliferative or hyperproliferative diseases, orimmunologically-mediated diseases (including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS)).

In one aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related,    diseases; nasal polyposis; fibroid lung, idiopathic interstitial    pneumonia, antittissive activity, treatment of chronic cough    associated with inflammatory conditions of the airways or iatrogenic    induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behçet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia greata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as leprornatous leprosy), Peridontal    disease, Sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle.

The compounds of the invention are also H1 antagonists and may be usedin the treatment of allergic disorders.

The compounds of the invention may also be used to control a sign and/orsymptom of what is commonly referred to as a cold (for example a signand/or symptom of a common cold or influenza or other associatedrespiratory virus infection).

According to a further feature of the invention there is provided acompound of formula (I) (for example a compound of formula (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptablesalt thereof or a solvate thereof, for use in a method of treatment of awarm blooded animal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there isprovided a method for modulating chemokine receptor activity (especiallyCCR3 receptor activity), or antagonising H1, in a warm blooded animal,such as man, in need of such treatment, which comprises administering tosaid animal an effective amount of a compound of the formula (I) (forexample a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig)or (Ih)), or a pharmaceutically acceptable salt thereof or a solvatethereof.

The invention also provides a compound of the formula (I) (for example acompound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)),or a pharmaceutically acceptable salt thereof or a solvate thereof, foruse as a medicament.

In another aspect the invention provides the use of a compound offormula (I) (for example a compound of formula (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereofor a solvate thereof, in the manufacture of a medicament for use intherapy (for example modulating chemokine receptor activity (especiallyCCR3 receptor activity), or antagonising H1, in a warm blooded animal,such as man).

The invention further provides the use of a compound of formula (I) (forexample a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig)or (Ih)), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia greata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle;    in a warm blooded animal, such as man.

In a further aspect a compound of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or apharmaceutically acceptable salt thereof, is useful in the treatment ofasthma {such as bronchial, allergic, intrinsic, extrinsic or dustasthma, particularly chronic or inveterate asthma (for example lateasthma or airways hyper-responsiveness)}; or rhinitis {including acute,allergic, atrophic or chronic rhinitis, such as rhinitis caseosa,hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitismedicamentosa; membranous rhinitis including croupous, fibrinous orpseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis}.

In a still further aspect a compound of formula (I) (for example acompound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)),or a pharmaceutically acceptable salt thereof, is useful in thetreatment of asthma.

The present invention also provides the use of a compound of formula (I)(for example a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig) or (Ih)), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of asthma orrhinitis.

The present invention further provides a method of treating a chemokinemediated disease state (especially a CCR3 mediated disease state,especially asthma) in a warm blooded animal, such as man, whichcomprises administering to a mammal in need of such treatment aneffective amount of a compound of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or apharmaceutically acceptable salt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceuticallyacceptable salt thereof or solvate thereof, for the therapeutictreatment of a warm blooded animal, such as man, in particularmodulating chemokine receptor (for example CCR3 receptor) activity orantagonising H1, said ingredient is normally formulated in accordancewith standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)(for example a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or asolvate thereof (active ingredient), and a pharmaceutically acceptableadjuvant, diluent or carrier. In a further aspect the present inventionprovides a process for the preparation of said composition whichcomprises mixing active ingredient with a pharmaceutically acceptableadjuvant, diluent or carrier. Depending on the mode of administration,the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.05 to 80% w, still morepreferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on totalcomposition.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by topical (such as to the lung and/or airways or to theskin), oral, rectal or parenteral administration. For these purposes thecompounds of this invention may be formulated by means known in the artinto the form of, for example, aerosols, dry powder formulations,tablets, capsules, syrups, powders, granules, aqueous or oily solutionsor suspensions, (lipid) emulsions, dispersible powders, suppositories,ointments, creams, drops and sterile injectable aqueous or oilysolutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous orintramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of the compound,preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of this invention,the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or apharmaceutically-acceptable salt thereof (hereafter Compound X), fortherapeutic or prophylactic use in humans:

mg/tablet (a) Tablet I Compound X 100 Lactose Ph. Eur. 179Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0(b) Tablet II Compound X 50 Lactose Ph. Eur. 229 Croscarmellose sodium12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (c) Tablet IIICompound X 1.0 Lactose Ph. Eur. 92 Croscarmellose sodium 4.0Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0 mg/capsule (d) CapsuleCompound X 10 Lactose Ph. Eur. 389 Croscarmellose sodium 100 Magnesiumstearate 1.0 (50 mg/ml) (e) Injection I Compound X 5.0% w/v Isotonicaqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

The invention will now be illustrated by the following non-limitingExamples in which, unless stated otherwise:

-   (i) when given, ¹H NMR data is quoted and is in the form of delta    values for major diagnostic protons, given in parts per million    (ppm) relative to tetramethylsilane (TMS) as an internal standard,    determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6    (CD₃SOCD₃), methanol-D4 (CD₃OD) or CDCl₃ as the solvent unless    otherwise stated;-   (ii) mass spectra (MS) were run with an electron energy of 70    electron volts in the chemical ionisation (CI) mode using a direct    exposure probe; where indicated ionisation was effected by electron    impact (EI) or fast atom bombardment (FAB) or electrospray (ESI);    where values for m/z are given, generally only ions which indicate    the parent mass are reported, and unless otherwise stated the mass    ion quoted is the positive mass ion—(M+H)⁺;-   (iii) the title and sub-title compounds of the examples and methods    were named using the ACD/Index name program version 4.55 from    Advanced Chemistry Development, Inc;-   (iv) unless stated otherwise, reverse phase HPLC was conducted using    a Symmetry, NovaPak or Xterra reverse phase silica column; and-   (v) the following abbreviations are used:

RPHPLC reverse phase HPLC DEAD diethyl-azodicarboxylate NMPN-methylpyrrolidone CDI N,N′-carbonyl diimidazole MTBE tert-butyl methylether DMF N,N-dimethylformamide HOBT 1-hydroxybenzotriazole Boc or BOCtert-butoxycarbonyl HPLC high pressure liquid chromatography EDCI Ethyldimethylaminopropyl carbodiimide TMEDA TertamethylethylenediaminePYBROP ™ bromo-tris-pyrrolidino-phosphonium hexafluorophosphate THFtetrahydrofuran DCM dichloromethane TFA trifluoroacetic acid m. pt.melting point DMSO dimethylsulfoxide Ac Acetate aq aqueous RT roomtemperature IPA iso-propyl alcohol LDA Lithium diisopropylamide equiv.equivalents

EXAMPLE 1A

N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide(an Example of a Compound of Formula (Ia)).

To a solution of 4-(3,4-dichlorophenoxy)-1,4′-bipiperidine (Method C;0.197 g) in dichloromethane (5 ml) was added 4-fluorobenzenesulfonylisocyanate (0.121 g) dropwise and the reaction was stirred undernitrogen for 12 hours. The solvent was removed under reduced pressureand the resulting product was purified by RPHPLC (Waters Xterra®column), (gradient, 75:25 0.2% aq ammonia/acetonitrile to 5:95 over 10mins) to give the title compound (60 mg; MS (M+H]⁺ (APCI+) 530/532).

¹H NMR (399.98 MHz, CD₃OD) δ 1.50-1.61 (m, 2H), 2.01-2.24 (m, 6H),2.64-2.73 (m, 2H), 3.25-3.43 (m, 5H), 4.42-4.50 (m, 2H), 4.64-4.71 (m,1H), 6.95-6.98 (m, 1H), 7.12-7.16 (m, 2H), 7.21-7.22 (m, 1H), 7.41-7.44(m, 1H), 7.90-7.95 (m, 2H).

The Examples 1B-1AV are examples of compounds of formula (Ia) and wereprepared using similar methodology to that of Example 1A.Recrystallisation was required after chromatography for severalExamples.

EXAMPLE 2A

N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenemethanesulfonamide(an Example of a Compound of Formula (Ia)).

To a stirred solution of para-nitrophenylchloroformate (0.141 g) indichloromethane (5 ml) was added dimethylaminopyridine (0.086 g). After2 minutes benzenemethanesulfonamide (0.120 g) was added followed bytriethylamine (0.078 g). After 30 minutes4-(3,4-dichlorophenoxy)-1,4′-bipiperidine (Method C; 0.230 g) was addedand the reaction was left to stir for 2 hours. The solvent was removedunder reduced pressure and the resulting product was purified by RPHPLC(Waters Xterra® column), (gradient, 90:10 0.2% aq ammonia/acetonitrileto 5:95 over 6 mins) to give the title compound (202 mg).

¹H NMR (399.98 MHz, CD₃OD) δ 1.30-1.43 (m, 2H), 1.73-1.84 (m, 4H),1.98-2.06 (m, 2H), 2.44-2.55 (m, 3H), 2.59-2.66 (m, 2H), 2.82-2.89 (m,2H), 4.36-4.42 (m, 3H), 4.41 (s, 2H), 6.88-6.91 (m, 1H), 7.09-7.10 (m,1H), 7.24-7.31 (m, 3H), 7.36-7.39 (m, 3H); plus 1 drop of 30% NaOD inD₂O.

ES+526/528

The Examples 2B-2X are examples of compounds of formula (Ia) and wereprepared using similar methodology to that of Example 2A.

EXAMPLE 3A

N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-N,4-dimethyl-benzenesulfonamide(an Example of a Compound of Formula (Ia) where R³ is not Hydrogen).

To a solution ofN-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide(Example 1B, 0.3 g) in methanol/dichloromethane (1:1, 40 ml) was added(trimethylsilyl)diazomethane (2M in hexanes) (5 ml) dropwise. Thereaction was stirred under nitrogen for 12 hours. The solvent wasremoved under reduced pressure and the resulting product was purified byRPHPLC (Waters Xterra® column), (gradient, 75:25 0.2% aq ammoniaacetonitrile to 5:95 over 6 mins) to give the title compound (83 mg).

¹H NMR (399.98 MHz, CD₃OD) δ 1.42-1.53 (m, 2H), 1.63-1.71 (m, 2H),1.82-1.96 (m, 4H), 2.31 (s, 3H), 2.39-2.47 (m, 2H), 2.48-2.57 (m, 1H);2.72-2.79 (m, 2H), 2.93-3.01 (m, 2H), 3.69 (s, 3H), 4.20-4.26 (m, 2H),4.27-4.34 (m, 1H), 6.77-6.81 (m, 1H), 7.00 (d, 1H), 7.21-7.29 (m, 3H),7.65-7.68 (m, 2H)

ES+540/542; m. pt. 151-153° C.

EXAMPLE 4A

N-Benzoyl-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (anExample of a Compound of Formula (Ib)).

Benzoyl sulfamoyl chloride (DE931225, (1955) Chemical Abstracts 1956,50, 7861a; 248 mg) was dissolved in THF (5 ml) and cooled to −78° C.Triethylamine (170 μl) was added dropwise over 160s and the solution wasstirred for 25 min. 4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (Method C;329 mg) in THF (5 ml) was added dropwise over 35 min. Water was addedthen the mixture was evaporated. The residue was purified by RPHPLC(Waters Xterra® Column, eluant 0.1% aq ammonium acetate:acetonitrile75-5:25-95) to give the title compound (37 mg; MS [M+H]⁺ (APCI+)512/514).

¹H NMR (399.98 MHz, DMSO) δ 1.59 (qd, 2H), 1.74-1.84 (m, 2H), 1.96 (d,2H), 2.06 (d, 2H), 2.76 (t, 2H), 2.86-3.03 (m, 3H), 3.08-3.17 (m, 2H),3.71 (d, 2H), 4.57-4.64 (m, 1H), 7.02 (dd, 1H), 7.32 (d, 1H), 7.37 (t,2H), 7.45 (t, 1H), 7.53 (d, 1H), 7.92 (d, 2H).

EXAMPLE 5A

N-Benzoyl-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine)-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

4-(2,4-Dichloro-3-methylphenoxy)-1,4′-bipiperidine (see Method C; 240mg) was dissolved in dichloromethane (10 ml). Triethylamine (107 μl) wasadded followed by benzoyl sulfamoyl chloride (154 mg). The solution wasstirrred for 12 h and then concentrated. The residue was purified by byRPHPLC (Waters Xterra® column), (gradient, 90:10 0.2% aqammonia/acetonitrile to 5:95 over 6 mins) to give the title compound.(70 mg, MS [M+H]⁺ (APCI+) 526/528; m.pt. 223° C.)

¹H NMR (399.98 MHz, CD₃OD) δ 8.00-8.03 (m, 2H), 7.38-7.43 (m, 1H),7.31-7.36 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 4.45-4.52 (m, 1H),3.80-3.87 (m, 2H), 2.84-2.92 (m, 2H), 2.73-2.81 (m, 2H), 2.51-2.58 (m,2H), 2.44 (s, 3H), 2.38-2.44 (m, 1H), 1.91-2.03 (m, 4H), 1.80-1.89 (m,2H), 1.59-1.70 (m, 2H); plus 1 drop of 30% NaOD in D₂O.

The Examples 5B-5E are examples of compounds of formula (Ia) and wereprepared using similar methodology to that of Example 5A.

EXAMPLE 6A

trans4-Chloro-N-[[(4-[(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]-carbonyl]-benzenesulfonamide(an Example of a Compound of Formula (Ic)).

Sodium 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate(Method F, 111 mg), EDCI (99 mg), HOBT (97 mg), DMAP (32 mg) andp-chlorobenzenesulfonamide (98 mg) were combined in DMF (3 ml) andstirred overnight. The solvent was evaporated and the residue waspurified by RPHPLC (Waters Xterra® Column, eluant 0.1% aqueous ammoniumacetate:acetonitrile 75-25:25-75) to give the title compound (18 mg; MS[M+H]⁺ (APCI+) 545/547/549).

¹H NMR (399.98 MHz, DMSO) δ 1.23 (q, 2H), 1.35 (q, 2H), 1.74-1.97 (m,7H), 2.02-2.11 (m, 21), 2.88-3.07 (m, 4H), 3.09-3.21 (m, 2H), 4.56-4.67(m, 1H), 7.02 (dd, 1H), 7.33 (d, 1H), 7.46 (d, 2H), 7.53 (d, 1H), 7.73(d, 2H).

EXAMPLE 7A

N-Benzoyl-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide (anExample of a Compound of Formula (Id)).

4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide (Method H,200 mg) and triethylorthobenzoate (3 ml) were heated at 150° C. for 16h, then allowed to reach ambient temperature. 2M HCl (2 ml) was addedand the resulting solution was stirred for 4 h. The volatiles wereevaporated and the residue was purified by chromatography (24:1dichloromethane: methanol) followed by RPHPLC (Waters Xterra® column),(gradient, 75:25 0.2% aq ammonia/acetonitrile to 5:95 over 6 mins) togive the title compound (m.pt. 65-80° C.; MS [M+H]⁺ (ES+) 476/478).

¹H NMR (399.98 MHz, DMSO) δ 1.42 (2H, d), 1.58 (2H, d), 1.76 (2H, d),1.92 (2H, d), 2.39 (2H, t), 2.72-2.78 (2H, m), 2.81-2.94 (3H, m),3.79-4.22 (2H, m), 4.42 (1H, t), 6.98 (1H, dd), 7.25 (1H, d), 7.44-7.52(3H, m), 7.56-7.68 (1H, m), 7.83-7.92 (2H, m).

EXAMPLE 8A

N-(3,4-Dichlorobenzoyl)-4-(3,4-dichlorophenoxy)-(1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (Method G,200 mg), 3,4 dichlorobenzoylchloride (102 mg) and triethylamine (0.07ml) were stirred together in dichloromethane (10 ml) at ambienttemperature for 24 hours. The solvent was evaporated and the resultingproduct was purified by RPHPLC (Waters Xterra® column), (gradient, 75:250.2% aq ammonia/acetonitrile to 5:95 over 6 mins) to give the titlecompound (22 mg; m.pt. 166-167° C.; MS APCI 580/582/584 (M+H)).

¹H NMR (399.98 MHz, DMSO) δ 1.57-1.79 (m, 4H), 1.89-2.17 (m, 5H),2.60-2.76 (m, 2H), 3.06-3.25 (m, 2H), 3.36-3.60 (m, 2H), 3.60-3.76 (m,2H), 4.54-4.87 (m, 1H), 6.93-7.11 (m, 1H), 6.93-7.11 (m, 1H), 7.30-7.40(m, 1H), 7.49-7.66 (m, 2H), 7.85 (d, 1H), 8.12 (s, 1H).

The Examples 8B-8F are examples of compounds of formula (Ib) and wereprepared using similar methodology to that of Example 8A.Recrystallisation was required after chromatography for severalExamples.

EXAMPLE 9A

4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

1,1-Dimethylethyl[4-(3,4-dichlorophenoxy)-1,4′-bipiperidin-1′-yl]sulfonylcarbamate(Method L; 400 mg) and triethylamine (0.5 ml) in dichloromethane (5 ml)at ambient temperature were treated with 4-methylbenzoylchloride (163mg). The mixture was stirred overnight, the solvent was evaporated andthe residue was dissolved in DMSO (1 ml) and purified by HPLC (WatersXTerra® column) (acetonitrile/aqueous ammonia gradient) to give thetitle compound as a white solid (70 mg).

MS [M+H]⁺ (APCI+) 526/528 (M+H) ¹H NMR δ (DMSO) 1.51-1.61 (2H, m),1.67-1.81 (2H, m), 1.86-1.96 (2H, m), 1.98-2.08 (2H, m), 2.33 (3H, s),2.71-2.92 (5H, m), 2.98-3.09 (2H, m), 3.72 (2H, d), 4.52-4.61 (1H, m),7.01 (1H, dd), 7.20 (2H, d), 7.30 (1H, d), 7.52 (1H, d), 7.82 (2H, d).

The Examples 9B and 9C are examples of compounds of formula (Ib) andwere prepared using similar methodology to that of Example 9A.

EXAMPLE 10A

N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide,Sodium Salt (an Example of a Compound of Formula (Ia)).

ToN-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide(0.05 g) was added 0.1M sodium hydroxide (0.949 ml) and methanol (5 ml).The solution was stirred until all of the starting material haddissolved. The solvent was removed under reduced pressure to give thetitle compound.

Mpt 201° C. MS [M+H]⁺ (APCI+) 526/528 ¹H NMR δ (CD₃OD) 1.28-1.42 (2H,m), 1.70-1.82 (4H, m), 1.96-2.04 (2H, m), 2.35 (3H, s), 2.43-2.54 (3H,m), 2.56-2.66 (2H, m), 2.80-2.87 (2H, m), 4.34-4.42 (3H, m), 6.87-6.90(1H, m), 7.09-7.10 (1H, m), 7.19-7.23 (2H, m), 7.35-7.38 (1H, m),7.75-7.79 (2H, m).

The Examples 10B-10D are examples of compounds of formula (Ia) and wereprepared using similar methodology to that of Example 10A.

EXAMPLE 11A

4-(3,4-Dichlorophenoxy)-N-[(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

To a solution of1,1-dimethylethyl[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl]-carbamate(Method L; 0.305 g) in dichloromethane was added1,2-dihydro-1-oxo-4-isoquinolinecarbonyl chloride (0.147 g, preparedfrom the corresponding acid by treatment with thionyl chloride atreflux) followed by triethylamine (0.097 ml) and the reaction wasstirred under nitrogen for 12 h. The solvent was removed under reducedpressure with the resulting product dissolved in DMSO and purified byHPLC (Waters XTerra® column), (gradient, 75% aqueous (0.2%ammonia)/acetonitrile decreasing to 5% over 10 min) to give1,1-dimethylethyl[[4-(3,4dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl][(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-carbamate.(MS [M+H]⁺ (ES+) 679/681).

1,1-Dimethylethyl[[4-(3,4dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl][(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-carbamatewas dissolved in dichloromethane (10 ml) followed by the addition oftrifluoroacetic acid, (3 ml) and allowed to stir under nitrogen for 12h. The solvent was removed under reduced pressure and the resultingproduct was dissolved in DMSO and purified by HPLC (Waters XTerra®column), (gradient, 90% aqueous (0.2% ammonia)/acetonitrile decreasingto 5% over 10 min) to give the title compound (0.028 g)

m.pt. 200° C. MS [M+H]⁺ (ES+) 579/581 ¹H NMR (399.98 MHz) δ (CD₃OD plus1 drop NaOD) 1.58-1.69 (2H, m), 1.71-1.81 (2H, m), 1.92-2.05 (4H, m),2.37-2.46 (1H, m), 2.48-2.56 (2H, m), 2.76-2.90 (4H, m), 0.84-3.90 (2H,m), 4.35-4.42 (1H, m), 6.86-6.90 (1H, m), 7.08 (1H, d), 7.30-7.34 (1H,m), 7.37 (1H, d), 7.49-7.54 (1H, m), 8.27-8.31 (1H, m), 8.44 (1H, s),8.75 (1H, d)

EXAMPLE 12A

N-(Cyclohexylcarbonyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

To a solution of1,1-dimethylethyl[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl]-carbamate(Method L; 0.305 g) in chloroform was added cyclohexanecarbonyl chloride(0.094 ml), triethylamine (0.097 ml) and dimethylaminopyridine (0.086g). The reaction mixture was heated in a CEM Discover microwave at 300 Wfor 5 seconds reaching a temperature of 50° C.; pressure developed. Thesolvent was removed under reduced pressure and the resulting product wasdissolved in DMSO and purified by HPLC (Waters XTerra® column),(gradient, 90% aqueous (0.2% ammonia)/acetonitrile decreasing to 5% over10 min) to give the title compound (0.176 g) as a foam.

MS [M+H]⁺ (ES+) 518/520 ¹H NMR (399.98 kHz) δ (CD₃OD) 1.10-1.38 (5H, m),1.44-1.62 (3H, m), 1.65-1.76 (6H, m), 1.82-1.89 (2H, m), 1.90-1.98 (2H,m), 2.07-2.16 (1H, m), 2.41-2.57 (3H, m), 2.72-2.86 (4H, m), 3.74-3.80(2H, m), 4.30-4.37 (1H, m), 6.78-6.81 (1H, m), 7.02 (1H, d), 7.28 (1H,d)

EXAMPLE 13A

4-(3,4-Dichlorophenoxy)-N-(2-methyl-1-oxopropyl)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

To a solution of4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (Method G;0.408 g) in dichloromethane (5 ml) was added 2-methyl-propanoyl chloride(0.126 ml), triethylamine (0.167 ml) and dimethylaminopyridine (0.147g). The reaction was heated in a CEM Discover microwave at 50° C. using50 W of power for 10 minutes. The solvent was removed under reducedpressure and the resulting product was dissolved in DMSO and purified byHPLC (Waters XTerra® column), (gradient, 90% aqueous (0.1% aqueousammonium acetate)/acetonitrile decreasing to 5% over 10 min) to give thetitle compound (0.152 g) as a foam.

MS [M+H]⁺ (ES+) 478/480 ¹H NMR (399.98 MHz) δ (CD₃OD) 1.30 (6H, d),1.75-1.91 (2H, m), 1.97-2.11 (2H, m), 0.13-2.32 (4H, m), 2.65 (1H,septet), 2.77-2.99 (3H, m), 3.02-3.12 (2H, m), 3.12-3.25 (2H, m),4.04-4.15 (2H, m), 4.62-4.72 (1H, m), 7.09 (1H, dd), 7.31 (1H, d), 7.57(1H, d)

EXAMPLE 14A

4-(3,4-Dichlorophenoxy)-N-(2-phenylacetyl)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

To a solution 4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide(Method G; 0.100 g) in THF (2 ml) was added potassium tert butoxide(0.083 g) followed after 1 h by phenylacetyl chloride (0.097 ml). After12 h the solvent was evaporated and the resultant product was dissolvedin methanol and loaded onto an Isolute® SCX cartridge which was washedwith methanol and eluted with 10% ammonia in methanol. The solvent wasevaporated and the residue was dissolved in DMSO and purified by HPLC(Waters XTerra® column), (gradient, 90% aqueous (0.2%ammonia)/acetonitrile decreasing to 75% over 10 min) to give the titlecompound (0.01 g).

MS [M+H]⁺ (ES+) 526/528 ¹H NMR (299.945 MHz) δ (CD₃OD plus 1 drop NaOD)1.45-1.59 (2H, m), 1.70-1.89 (4H, m), 1.96-2.08 (2H, m), 2.23-2.35 (1H,m), 2.43-2.63 (4H, m), 2.77-2.88 (2H, m), 3.45 (2H, s), 3.66-3.75 (2H,m), 4.35-4.44 (1H, m), 6.88-6.94 (1H, m), 7.10-7.13 (1H, m), 7.14-7.30(3H, m), 7.33-7.42 (3H, m)

EXAMPLE 15A

N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide(an Example of a Compound of Formula (Ia)).

To a solution 4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide(Method H; 0.372 g) in THF (5 ml) was added potassium tert butoxide(0.337 g) followed after 1 h by 2-propanesulfonyl chloride (0.337 ml).After a further 2 h aqueous ammonium chloride was added and THF wasevaporated to leave a precipitate which was collected. The precipitatewas purified by HPLC (Waters XTerra® column), (gradient, 95% aqueous(0.2% ammonia)/acetonitrile decreasing to 50% over 10 min) to give thetitle compound (0.061 g).

MS [M+H]⁺ (ES+) 478/480 ¹H NMR (399.98 MHz) δ (CD₃OD plus 1 drop NaOD)1.19 (6H, d), 1.23-1.37 (2H, m), 1.62-1.70 (2H, m), 1.71-1.78 (2H, m),1.88-1.96 (2H, m), 2.34-2.47 (3H, m), 2.48-2.60 (2H, m), 2.72-2.80 (2H,m), 3.38-3.46 (1H, m), 4.27-4.37 (3H, m), 6.79 (1H, dd), 6.99 (1H, d),7.28 (1H, d)

EXAMPLE 16A

4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[1,4′-bipiperidine)-1′-sulfonamideSodium Salt (an Example of a Compound of Formula (Ie)).

4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (Method L;582 mg), toluenesulfonyl chloride (380 mg) and DMAP (180 mg) werecombined and dissolved in dichloromethane (10 ml). Triethylamine (0.3ml) was added, followed after 35 min by a second portion oftriethylamine (0.3 ml). The solution was stirred for 21 h and thenconcentrated. The residue was triturated with methanol and then THF togive a solid (0.65 g). A portion of the product (0.34 g) was dissolvedin warm DMSO (30 ml). To this solution was added aqueous sodiumhydroxide (1M, 6 ml) followed by water (200 ml). The solution wasallowed to cool overnight and the title compound was collected (175 mg).

m. pt. 242-243° C. MS [M+H]⁺ (ES+) 562/564

¹H NMR (399.98 MHz) δ_((DMSO))1.27 (2H, qd), 1.51-1.60 (2H, m), 1.65(2H, d), 1.88-1.94 (2H, m), 2.23 (1H, tt), 2.31 (3H, s), 2.32-2.43 (4H,m), 2.68-2.75 (2H, m), 3.33-3.38 (2H, m), 4.37-4.43 (1H, m), 6.98 (1H,dd), 7.18 (2H, d), 7.25 (1H, d), 7.48 (1H, d), 7.60 (2H, d)

Example 16B (an example of a compound of formula (Ie)) was preparedusing similar methodology to that of Example 16A and recrystallisationwas required after chromatography.

MS [M + H]⁺ m. pt. Example Compound (ES+) ¹H NMR δ ° C. 1B N-[[4-(3,4-526/528 (CD₃OD) 1.18-1.30(m, 2H), 1.62-1.74(m, 4H); 1.87-1.95228.1-228.6 Recrystallisation Dichlorophenoxy)[1,4′- (m, 2H), 2.26(s,3H), 2.32-2.43(m, 3H), 2.48-2.57(m, solvent DMSO bipiperidin]-1′- 2H),2.70-2.76(m, 2H), 4.25-4.33(m, 3H), 6.77-6.81(m, yl]carbonyl]-4- 1H),6.98-7.00(m, 1H), 7.11-7.15(m, 2H), 7.28(d, 1H),methyl-benzenesulfonamide 7.65-7.68(m, 2H); 0.7 ml of CD₃OD plus 1 dropof NaOD (30% in D₂O) 1C N-[[4-(2,4-Dichloro-3- 540/542 (CD₃OD)1.50-1.61(m, 2H), 1.97-2.04(m, 2H), 2.08-2.21 methylphenoxy)[1,4′- (m,4H), 2.36(s, 3H), 2.47(s, 3H), 2.64-2.73(m, 2H), 3.22- bipiperidin]-1′-3.40(m, 5H), 4.40-4.49(m, 2H), 4.70-4.76(m, 1H), 7.01- yl]carbonyl]-4-7.03(m, 1H), 7.22-7.24(m, 2H), 7.27-7.29(m, 1H), 7.76-methyl-benzenesulfonamide 7.79(m, 2H). 1D 4-Chloro-N-[[4-(3,4-546/548/550 (CD₃OD) 1.18-1.28(m, 2H), 1.61-1.75(m, 4H), 1.87-1.94Recrystallisation dichlorophenoxy)[1,4′- (m, 2H), 2.33-2.43(m, 3H),2.47-2.58(m, 2H), 2.70-2.77 solvent methanol bipiperidin]-1′- (m, 2H),4.25-4.32(m, 3H), 6.78-6.80(m, 1H), 6.99-7.00 yl]carbonyl]- (m, 1H),7.27-7.34(m, 3H), 7.74-7.77(m, 2H); 0.7 ml of benzenesulfonamide CD₃ODplus 1 drop of NaOD(30% in D₂O) 1E N[[4-(3,4- 526/528 (CD₃OD)1.50-1.61(m, 2H), 2.01-2.11(m, 4H), 2.12-2.24 160-161Dichlorophenoxy)[1,4′- (m, 2H), 2.63-2.73(m, 2H), 2.64(s, 3H),3.25-3.43(m, bipiperidin]-1′- 5H), 4.43-4.52(m, 2H), 4.63-4.69(m, 1H),6.94-6.98(m, yl]carbonyl]-2- 1H), 7.20-7.25(m, 3H), 7.30-7.35(m, 1H),7.41-7.44(m, methyl-benzenesulfonamide 1H), 7.95-7.99(m, 1H) 1FN-[[4-(3,4- 512/514 (CD₃OD) 1.17-1.33(m, 2H), 1.59-1.76(m, 4H),1.86-1.96 207-214 Dichlorophenoxy)[1,4′- (m, 2H), 2.31-2.45(m, 3H),2.47-2.59(m, 2H), 2.69-2.78 bipiperidin]-1′- (m, 2H), 4.24-4.34(m, 3H),6.77-6.81(m, 1H), 6.98-7.00 yl]carbonyl]- (m, 1H), 7.26-7.36(m, 4H),7.76-7.81(m, 2H); plus 1 drop benzenesulfonamide of 30% NaOD 1GN-[[4-(4-Chloro-2- 506/508 (CD₃OD) 1.49-1.61(m, 2H), 1.99-2.05(m, 2H),2.06-2.14 methylphenoxy)[1,4′- (m, 2H), 2.15-2.23(m, 2H), 2.22(s, 3H),2.36(s, 3H), 2.64- bipiperidin]-1′- 2.73(m, 2H), 3.22-3.39(m, 5H),4.39-4.48(m, 2H), 4.60- yl]carbonyl]-4- 4.66(m, 1H), 6.91-6.95(m, 1H),7.10-7.17(m, 2H), 7.21- methyl-benzenesulfonamide 7.25(m, 2H),7.75-7.80(m, 2H) 1H N-[[4-(3,4- 546/548 (CD₃OD) 1.17-1.36(m, 2H),1.59-1.76(m, 4H), 1.85-1.97 Dichlorophenoxy)[1,4′- (m, 2H), 2.31-2.45(m,3H), 2.47-2.59(m, 2H), 2.68-2.78 bipiperidin]-1′- (m, 2H), 4.24-4.37(m,3H), 6.76-6.81(m, 1H), 6.98-7.00 yl]carbonyl]-2-chloro- (m, 1H),7.21-7.36(m, 4H), 7.94-8.01(m, 1H); plus 1 drop benzenesulfonamide of30% NaOD in D₂O 1I N-[[4-(2,4-Dichloro-3- 560/562/564 (CD₃OD)1.19-1.31(m, 2H), 1.68-1.79(m, 4H), 1.84- methylphenoxy)[1,4′- 1.93(m,2H), 2.35(s, 3H), 2.37-2.46(m, 3H), 2.48-2.58 bipiperidin]-1′- (m, 2H),2.71-2.79(m, 2H), 4.24-4.34(m, 2H), 4.35-4.41 yl]carbonyl]-4-chloro- (m,1H), 6.83-6.87(m, 1H), 7.14-7.17(m, 1H), 7.30-7.33 benzenesulfonamide(m, 2H), 7.74-7.77(m, 2H) 1 drop of 30% NaOD added in D₂O 1JN-[[4-[(3,4- 524/526 (CDCl₃) 7.79(3H, d), 7.32(1H, d), 7.20(2H, d),7.13(1H, 147-172 dichlorophenyl)methyl] d), 6.89(1H, dd), 4.56(2H, s),3.55(2H, d), 3.07(1H, s), 2.62 [1,4′-bipiperidin]- (4H, s), 2.35(5H, s),2.02(2H, d), 1.66(7H, d) 1′-yl]carbonyl]-4- methyl-benzenesulfonamide 1K2-Chloro-N[[4-[(3,4- 544/546/548 (CD₃OD) 8.07(1H, dd), 7.47-7.31(5H, m),7.09(1H, dd), 212-239 dichlorophenyl)methyl] 2.91(2H, d), 2.91(2H, d),2.59(2H, t), 2.52(2H, d), 2.43- [1,4′-bipiperidin]-1′- 2.34(1H, m),2.15(2H, t), 1.77(2H, d), 1.62(2H, d), 1.57- yl]carbonyl]- 1.44(1H, m),1.29(4H, d) benzenesulfonamide 1L 4-Chloro-N-[[4-[(3,4- 542/544/546(CD₃OD) 1.18-1.39(4H, m), 1.46-1.59(1H, m), 1.62(2H, 164-184dichlorophenyl)methyl] d), 1.77(2H, d), 2.15(2H, dd), 2.34-2.44(1H, m),2.49- [1,4′-bipiperidin]-1′- 2.65(4H, m), 2.90(2H, d), 4.34(2H, s),7.09(1H, dd), 7.32 yl]carbonyl]- (1H, d), 7.38-7.43(3H, m), 7.84(2H, dt)benzenesulfonamide 1M N-[[4-[(5-Chloro-2- 493/495 (DMSO) 8.20(1H, d),7.81(1H, dd), 7.67(2H, d), 7.23 (2H, pyridinyl)oxy][1,4′- d), 6.87(1H,d), 5.09-5.01(1H, m), 4.16(2H, d), 3.13-3.00 bipiperidin]-1′- (1H, m),2.94-2.77(1H, m), 2.62-2.53(5H, m), 2.33(3H, yl]carbonyl]-4- s),2.13-2.02(2H, m), 1.85-1.75(4H, m), 1.37-1.23(2H,methyl-benzenesulfonamide m) 1N 2-Chloro-N-[[4-(2- 530/532 (CD₃OD)1.44-1.56(m, 2H), 1.90-1.97(m, 2H), 1.98- chloro-4- 2.15(m, 4H),2.56-2.66(m, 2H), 3.20-3.40(m, 5H), fluorophenoxy)[1,4′- 4.35-4.46(m,2H), 4.54-4.64(m, 1H), 6.93-6.99(m, bipiperidin]-1′- 1H), 7.07-7.11(m,1H), 7.14-7.17(m, 1H), 7.24-7.35 yl]carbonyl]- (m, 3H), 7.99-8.02(m, 1H)benzenesulfonamide 1O N-[[4-(2-Chloro-4- 510/512 (CD₃OD) 1.27-1.37(m,2H), 1.78-1.87(m, 4H), 1.93- 221-222 fluorophenoxy)[1,4′- 2.02(m, 2H),2.35(s, 3H), 2.42-2.53(m, 3H), 2.57-2.67 bipiperidin]-1′- (m, 2H),2.82-2.89(m, 2H), 4.34-4.45(m, 3H), 6.97- yl]carbonyl]-4- 7.03(m, 1H),7.08-7.12(m, 1H), 7.16-7.20(m, 1H), methyl-benzenesulfonamide7.20-7.24(m, 2H), 7.74-7.77(m, 2H) 0.7 ml of CD3OD plus 1 drop ofNaOD(30% in D2O) 1P N-[[4-(2,4-Dichloro-3- ES+ (CD₃OD) 1.42-1.53(m, 2H),1.89-1.95(m, 2H), 2.01- methylphenoxy)[1,4′- 526/528 2.09(m, 4H),2.37(s, 3H), 2.55-2.65(m, 2H), 3.17-3.34 bipiperidin]-1′- (m, 5H),4.32-4.41(m, 2H), 4.61-4.67(m, 1H), 6.91- yl]carbonyl]- 6.94(m, 1H),7.20-7.22(m, 1H), 7.30-7.37(m, 3H), benzenesulfonamide 7.78-7.82(m, 2H)1Q N-[[4-(4- 492/494 (CD₃OD plus 1 drop NaOD) 1.27-1.39(2H, m),1.70-1.84 237-238 chlorophenoxy)[1,4′- (4H, m), 1.96-2.04(2H, m),2.36(3H, s), 2.40-2.51, (3H, bipiperidin]-1′- m), 2.56-2.67(2H, m),2.79-2.87(2H, m), 4.31-4.42 yl]carbonyl]-4- (3H, m), 6.89(2H, d),7.20-7.24(4H, m), 7.76(2H, d) methyl- benzenesulfonamide 1RN-[[4-(2,4-dichloro-3- 540/542 (CD₃OD plus 1 drop NaOD) 1.27-1.41(2H,m), 1.78-1.88 methylphenoxy)[1,4′- (4H, m), 1.93-2.02(2H, m),2.44-2.55(3H, m), 2.44(3H, bipiperidin]-1′- s), 2.57-2.67(2H, m),2.66(3H, s), 2.81-2.89(2H, m), yl]carbonyl]-2- 4.35-4.51(3H, m),6.95(1H, d), 7.19-7.34(4H, m), 7.94- methyl-benzenesulfonamide 7.97(1H,m) 1S N-[[4-(2,4-dichloro-3- (CDCl₃) 1.61(2H, q), 2.07(4H, t), 2.28(2H,t), 2.38(3H, s), fluorophenoxy)[1,4′- 2.70(2H, t), 2.93-3.05(1H, m),3.12(2H, t), 3.18-3.28 bipiperidin]-1′- (2H, m), 4.45(2H, d),4.60-4.67(1H, m), 6.79(1H, dd), yl]carbonyl]-4- 7.24(2H, d), 7.30(1H,d), 7.80(2H, d) methyl-benzenesulfonamide 1T N-[[4-(4-chloro-2- 506/508(CD₃OD) 1.40-1.55(3H, m), 1.91-2.03(6H, m), 2.13(3H, 161methylphenoxy)[1,4′- s), 2.56(3H, s), 2.56-2.64(3H, m), 3.23-3.30(3H,m), bipiperidin]-1′- 4.34-4.44(2H, m), 4.50-4.56(1H, m), 6.80(1H, d),7.00- yl]carbpnyl]-2- 7.07(2H, m), 7.11-7.16(2H, m), 7.20-7.25(1H, m),7.84- methyl-benzenesulfonamide 7.88(1H, m) 1U 2-chloro-N-[[4-(4-526/528 (CD₃OD) 1.51-1.64(3H, m), 2.05(5H, d), 2.71(3H, t), 164chloro-2- 3.33-3.40(4H, m), 4.44-4.56(3H, m), 4.61-4.68(2H,methylphenoxy)[1,4′- m), 6.94(1H, d), 7.12(1H, dd), 7.34(1H, d),7.35(1H, d), bipiperidin]-1′- 7.38(1H, dd), 7.42-7.45(1H, m), 8.09(1H,dd) yl]carbonyl] benzenesulfonamide 1V 4-chloro-N-[[4-(4- 526/528(CD₃OD) 1.68-1.82(2H, m), 2.09-2.15(4H, m), 2.17- 160 chloro-2- 2.21(3H,m), 2.37-2.48(2H, m), 2.59-2.71(2H, m), 2.99- methylphenoxy)[1,4′-3.14(3H, m), 3.40-3.52(2H, m), 4.49-4.63(3H, m), bipiperidin]-1′-6.68(1H, d), 7.07-7.16(2H, m), 7.36(2H, d), 7.88(2H, d) yl]carbonyl]-benzenesulfonamide 1W N-[[4-(2,4- 526/528 (CD₃OD plus 1 drop NaOD)1.27-1.40(2H, m), 1.77-1.88 dichlorophenoxy)[1,4′- (4H, m),1.94-2.03(2H, m), 2.35(3H, s), 2.42-2.55(3H, bipiperidin]-1′- m),2.56-2.68(2H, m), 2.80-2.88(2H, m), 4.33-4.44 yl]carbonyl]-4- (2H, m),4.45-4.52(1H, m), 7.08(1H, d), 7.21-7.25(3H, methyl-benzenesulfonamidem), 7.38(1H, d), 7.76(2H, d) 1X N-[[4-(3- 492/494 (CD₃OD plus 1 dropNaOD) 1.30(2H, q), 1.71-1.83(4H, 172-178 chlorophenoxy)[1,4′- m),1.94-2.04(2H, m), 2.34(3H, s), 2.40-2.50(3H, m), bipiperidin]-1′-2.56-2.68(2H, m), 2.75-2.83(2H, m), 4.32-4.43(3H, yl]carbonyl]-4- m),6.81-6.89(3H, m), 7.22(1H, t), 7.22(2H, d), 7.76(2H, d) methyl-benzenesulfonamide 1Y 2-chloro-N-[[4-(3- 512/514 (CD₃OD plus 1 dropNaOD) 1.30-1.43(2H, m), 1.72-1.86 180-186 chlorophenoxy)[1,4′ (4H, m),1.97-2.03(2H, m), 2.42-2.53(3H, m), 2.58- bipiperidin]-1′- 2.67(2H, m),2.80-2.87(2H, m), 4.35-4.46(3H, m), 6.85- yl]carbonyl]- 6.94(3H, m),7.22(1H, t), 7.32-7.46(3H, m), 8.08(1H, dd) benzenesulfonamide 1ZN-[[4-(3- 478/480 (CD₃OD plus 1 drop NaOD) 1.26-1.41(2H, m), 1.69-1.85197-206 chlorophenoxy)[1,4′- (4H, m), 1.95-2.04(2H, m), 2.41-2.53(3H,m), 2.57- bipiperidin]-1′- 2.68(2H, m), 2.79-2.88(2H, m), 4.34-4.46(3H,m), 6.83- yl]carbonyl]- 6.94(3H, m), 7.22(1H, dt), 7.39-7.46(3H, m),7.87-7.89 benzenesulfonamide (2H, m) 1AA 2-chloro-N-[[4-(3- 526/528(CD₃OD plus 1 drop NaOD) 1.32-1.43(2H, m), 1.76-1.86 223-234 chloro-2-(4H, m), 1.95-2.04(2H, m), 2.25(3H, s), 2.46-2.55(3H,methylphenoxy)[1,4′- m), 2.59-2.69(2H, m), 2.79-2.87(2H, m), 4.35-4.48bipiperidin]-1′- (3H, m), 6.88(1H, d), 6.93(1H, d), 7.08(1H, t),7.32-7.45 yl]carbdnyl]- (3H, m), 8.08(1H, dd) benzenesulfonamide 1ABN-[[4-(2-chloro-4- 510/512 (DMSO) 1.17-1.46(2H, m), 1.65-2.16(8H, m),2.57 (3H, s), 164-165 fluorophenoxy)[1,4′- 2.77-3.85(6H, m),4.12-4.32(2H, m), 7.12-7.34(5H, m), bipiperidin]-1′- 7.46(1H, dd),7.78(1H, d) yl]carbonyl]-2- methyl-benzenesulfonamide 1AC2-chloro-N-[[4-(2,4- 564/566/568 (DMSO) 1.20-1.50(2H, m), 1.69-2.30(7H,m), 2.88- 172-173 dichloro-3- 3.60(8H, m), 4.17-4.40(1H, m),7.10-7.27(1H, m), 7.27- fluorophenoxy)[1,4′- 7.44(3H, m), 7.57(1H, t),7.83-7.98(1H, m) bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 1AD4-chloro-N-[[4-(2,4- 564/566/568 (DMSO) 1.21-1.48(2H, m), 1.64-2.25(6H,m), 2.88- 167-168 dichloro-3- 3.40(9H, m), 4.10-4.41(1H, m), 7.18(1H,dd), 7.43(2H, fluorophenoxy)[1,4′- d), 7.56(1H, t), 7.67-7.85(2H, d)bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 1AEN-[[4-(2,4-dichloro-3- 544/546 (DMSO) 1.21-1.42(2H, m), 1.62-2.17(6H,m), 2.55(3H, 151-152 fluorophenoxy)[1,4′- s), 2.75-3.24(7H, m),4.09-4.35(2H, m), 4.60-4.87(1H, bipiperidin]-1′- m), 7.13-7.24(3.H, m),7.28-7.37(1H, m), 7.55(1H, t), yl]carbonyl]-2- 7.80(1H, d)methyl-benzenesulfonamide 1AF 2-chloro-N-[[4-(4- 512/514 (DMSO)1.23-1.53(2H, m), 1.62-2.39(7H, m), 2.92- 182-183 chlorophenoxy)[1,4′-3.68(6H, m), 4.13-4.44(2H, m), 4.44-4.91(1H, m), 6.95- bipiperidin]-1′-7.17(2H, m), 7.30-7.45(5H, m), 7.82-8.01(1H, m) yl]carbonyl]-benzenesulfonamide 1AH 4-chloro-N-[[4-(4- 512/514 (DMSO) 1.11-1.37(3H,m), 1.47-2.20(7H, m), 2.55- 249-250 chlorophenoxy)[1,4′- 3.24(6H, m),4.04-4.64(2H, m), 7.00(2H, d), 7.32(2H, d), bipiperidin]-1′- 7.39(2H,dt), 7.72(2H, dt) yl]carbonyl]- benzenesulfonamide 1AI N-[[4-(4- 492/494(DMSO) 1.14-1.43(2H, m), 1.64-2.16(6H, m), 2.55(3H, 153-154chlorophenoxy)[1,4′- s), 2.77-3.52(7H, m), 4.15-4.32(2H, m),4.42-4.71(1H, bipiperidin]-1′- m), 7.02(2H, d), 7.12-7.25(2H, m),7.25-7.39(3H, m), yl]carbonyl]-2- 7.78(1H, d) methyl-benzenesulfonamide1AJ 2-chloro-N-[[4-(2,4- 546/548/550 (DMSO) 1.22-1.49(2H, m),1.65-2.27(6H, m), 2.94- 162-163 dichlorophenoxy)[1,4′- 3.62(8H, m),4.15-4.43(2H, m), 7.20-7.47(5H, m), 7.62 bipiperidin]-1′- (1H, s),7.83-8.02(1H, m) yl]carbonyl]- benzenesulfonamide 1AK4-chloro-N-[[4-(2,4- 546/548/550 (DMSO) 1.14-1.50(2H, m), 1.66-2.23(6H,m), 2.83- 169-170 dichlorophenoxy)[1,4′- 3.48(9H, m), 4.19-4.31(1H, m),7.29(2H, d), 7.36-7.45 bipiperidin]-1′- (2H, m), 7.61(1H, d)7.68-7.88(2H, m) yl]carbonyl] benzenesulfonamide. 1AL N-[[4-(2,4-526/528 (CD₃OD) 1.73-2.06(6H, m), 2.42-2.63(6H, m), 2.66(3H, 165-166dichlorophenoxy)[1,4′- s), 2.78-2.92(3H, m), 4.35-4.54(3H, m), 7.08(1H,d), bipiperidin]-1′- 7.19-7.26(3H, m), 7.28-7.34(1H, m), 7.39(1H, d),7.91- yl]carbonyl]-2- 8.02(1H, m) methyl-benzenesulfonamide 1AM2-chloro-N-[[4-(3,4- 514/516 (DMSO) 1.28-1.47(2H, m), 1.59-2.40(6H, m),2.90- 165-166 difluorophenoxy)[1,4′- 3.60(7H, m), 4.16-4.42(2H, m),4.44-4.92(1H, m), 6.77- bipiperidin]-1′- 6.92(1H, m), 7.07-7.45(5H, m),7.81-7.98(1H, m) yl]carbonyl]- benzenesulfonamide 1AN N-[[4-(3,4- 494(DMSO) 1.20-1.48(2H, m), 1.56-2.27(6H, m), 2.55(3H, 147-148difluorophenoxy)[1,4′- s), 2.86-3.57(8H, m), 4.04-4.64(2H, m),6.77-6.90(1H, bipiperidin]-1′- m), 7.11-7.46(5H, m), 7.75-7.88(1H, d)yl]carbonyl]-2- methyl-benzenesulfonamide 1AO N-[[4-(3,4- 494 (DMSO)1.18-1.44(2H, m), 1.57-2.20(6H, m), 2.53(3H, 140-141difluorophenoxy)[1,4′- s), 2.63-3.53(7H, m), 4.11-4.23(2H, m),4.38-4.67(1H, bipiperidin]-1′- m), 6.78-6.85(1H, m), 7.09-7.18(1H, m),7.22(2H, d), yl]carbonyl]-4- 7.34(1H, dd), 7.67(2H, d)methyl-benzenesulfonamide 1AP N-[[4-(3-chloro-2- 506/508 (CD₃OD plus 1drop NaOD) 1.23-1.36(2H, m), 1.80(4H, 206-210 methylphenoxy)[1,4′- d),1.93-2.03(2H, m), 2.22(3H, s), 2.32(3H, s), 2.42-2.52 bipiperidin]-1′-(3H, m), 2.58-2.67(2H, m), 2.73-2.80(2H, m), 4.33- yl]carbonyl]-4-4.45(3H, m), 6.84(1H, d), 6.90(1H, d), 7.08(1H, t), 7.21methyl-benzenesulfonamide (2H, d), 7.76(2H, d) 1AQ N-[[4-(3-chloro-2-492/494 (CD₃OD plus 1 drop NaOD) 1.28-1.45(2H, m), 1.79-1.89 173-186methylphenoxy)[1,4′- (4H, m), 1.97-2.08(2H, m), 2.26(3H, s),2.42-2.70(5H, bipiperidin]-1′- m), 2.79-2.89(2H, m), 4.37-4.48(3H, m),6.89(1H, d), yl]carbonyl]- 6.94(1H, d), 7.09(1H, td), 7.39-7.47(3H, m),7.87-7.92 benzenesulfonainide (2H, m) 1AR 3-chloro-N-[[4-(3,4-546/548/550 (CD₃OD) 1.23-1.44(4H, m), 1.70-1.87(4H, m), 1.99(2H, 145-155dichlorophenoxy)[1,4′- s), 2.49(2H, d), 2.56-2.70(1H, m), 2.83(2H, s),4.38(3H, bipiperidin]-1′- s), 6.88(1H, dd), 7.09(1H, d), 7.33-7.45(3H,m), 7.79 yl]carbonyl]- (1H, dd), 7.88(1H, d) benzenesulfonamide 1ASN-[[4-(2,4-dichloro-3- 544/546 (CD₃OD) 1.58(2H, td), 2.00-2.08(2H, m),2.16(4H, d), 147-169 methylphenoxy)[1,4′- 2.46(3H, s), 2.70(2H, t),3.32-3.46(4H, m), 4.46(2H, d), bipiperidin]-1′- 4.58(1H, s), 4.74(1H,s), 7.03(1H, d), 7.14(2H, t), 7.30 yl]carbonyl]-4-fluoro- (1H, d),7.88-7.94(2H, m) benzenesulfonamide 1AT 2-chloro-N-[[4-(2,4- 560/562/564(CD₃OD plus 1 drop NaOD) 1.28-1.45(2H, m), 1.77-1.88 216 dichloro-3-(4H, m), 1.94-2.02(2H, m), 2.45(3H, s), 2.46-2.56(3H,methylphenoxy)[1,4′- m), 2.58-2.68(2H, m), 2.82-2.89(2H, m), 4.36-4.51bipiperidin]-1′- (3H, m), 6.95(1H, d), 7.25(1H, d), 7.32-7.44(3H, m),8.08- yl]carbonyl]- 8.11(1H, m) benzenesulfonamide 1AUN-[[4-(3,4-dichloro-2- 540/2 (CD₃OD plus 1 drop NaOD) 1.28-1.41(2H, m),1.76-1.85 195-200 methylphenoxy)[1,4′- (4H, m), 1.96-2.05(2H, m),2.31(3H, s), 2.35(3H, s), 2.43- bipiperidin]-1′- 2.56(3H, m),2.57-2.67(2H, m), 2.77-2.85(2H, m), yl]carbonyl]-4- 4.34-4.47(3H, m),6.91(1H, d), 7.22(2H, d), 7.27(1H, d), methyl-benzenesulfonamide7.76(2H, d) 1AV 2-chloro-N-[[4-(3,4- 560/562/564 171 dichloro-2-methylphenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide2B 3-Cyano-N[[4-(3,4- 537/539 (CD₃OD) 1.27-1.40(m, 2H), 1.70-1.85(m,4H), 1.96- dichlorophenoxy)[1,4′- 2.04(m, 2H), 2.43-2.53(m, 3H),2.56-2,69(m, 2H), 2.79- bipiperidin]-1′- 2.86(m, 2H), 4.33-4.42(m, 3H),6.86-6.90(m, 1H), yl]carbonyl]- 7.07-7.09(m, 1H), 7.36-7.39(m, 1H),7.59-7.64(m, benzenesulfonamide 1H), 7.78-7.81(m, 1H), 8.13-8.16(m, 1H),8.21-8.22 (m, 1H); plus 1 drop of NaOD, 30% in D₂O 2C N-[[4-(3,4-580/582 (CD₃OD) 1.40-1.53(m, 2H), 1.91-1.97(m, 4H), 2.01- 170-180dichlorophenoxy)[1,4′- 2.16(m, 2H), 2.55-2.65(m, 2H), 3.17-3.36(m, 5H),4.33- bipiperidin]-1′- 4.42(m, 2H), 4.55-4.62(m, 1H), 6.84-6.89(m, 1H),yl]carbonyl]-3- 7.11-7.13(m, 1H), 7.33(d, 1H), 7.51-7.56(m, 1H), 7.63-(trifluoroniethyl)- 7.67(m, 1H), 8.02-8.05(m, 1H), 8.09(s, 1H)benzenesulfonamide 2D N-[[4-(3,4- 542/544 (CD₃OD plus 1 drop NaOD)1.28-1.40(2H, m), 1.70-1.84 dichlorophenoxy)[1,4′- (4H, m),1.96-2.04(2H, m), 2.42-2.53(3H, m), 2.56- bipiperidin]-1′- 2.66(2H, m),2.78-2.86(2H, m), 3.81(3H, s), 4.34-4.42 yl]carbonyl]-4- (3H, m),6.87-6.90(1H, m), 6.91-6.95(2H, m), 7.09(1H, methoxy-benzenesulfonamided), 7.37(1H, d), 7.79-7.83(2H, m) 2E N-[[4-(3,4- 566/568 (CD₃OD plus 1drop NaOD) 1.28-1.43(2H, m), 1.70-1.85 223-228 dichlorophenoxy)[1,4′-(4H, m), 1.96-2.05(2H, m), 2.43-2.54(3H, m), 2.57- bipiperidin]-1′-2.69(2H, m), 2.80-2.88(2H, m), 4.33-4.43(3H, m), 6.88yl]carbonyl]-2,4,5- (1H, dd), 7.09(1H, d), 7.20(1H, ddd), 7.37(1H, d),7.79 trifluoro- (1H, ddd) benzenesulfonamide 2F N-[[4-(3,4- 548/550(CD₃OD) 1.51-1.63(2H, m), 2.00-2.09(4H, m), 2.09- 212-222dichlorophenoxy)[1,4′- 2.27(3H, m), 2.65-2.76(2H, m), 3.32-3.46(4H, m),4.41- bipiperidin]-1′- 4.54(2H, m), 4.63-4.73(1H, m), 6.97(1H, dd),7.12- yl]carbonyl]-2,5- 7.24(3H, m), 7.43(1H, d), 7.59-7.63(1H, m)difluoro- benzenesulfonamide 2G N-[[4-(3,4- 555/557 (CD₃OD plus 1 dropNaOD) 1.25-1.34(2H, m), 1.66-1.77 194-196 dichlorophenoxy)[1,4′- (4H,m), 1.94-2.02(2H, m), 2.39-2.47(3H, m), 2.52- bipiperidin]-1′- 2.61(2H,m), 2.75-2.83(2H, m), 2.97(6H, s), 4.31-4.43 yl]carbonyl]-4- (3H, m),6.67-6.70(2H, m), 6.93(1H, dd), 7.14(1H, d), (dimethylamino)- 7.42(1H,d), 7.64-7.68(2H, m) benzenesulfonamide 2H N-[[4-(3,4- 542/544 (CD₃OD)1.28-1.41(2H, m), 1.71-1.84(4H, m), 1.96- 215-218 dichlorophenoxy)[1,4′-2.04(2H, m), 2.42-2.53(3H, m), 2.57-2.66(2H, m), 2.80- bipiperidin]-1′-2.87(2H, m), 3.89(3H, s), 4.35-4.44(3H, m), 6.88(1H, yl]carbonyl]-2-dd), 6.94-6.99(1H, m), 7.05-7.10(2H, m), 7.37(1H, d),methoxy-benzenesulfonamide 7.40-7.44(1H, m), 7.87(1H, dd) 2I4-bromo-N-[[4-(3,4- 590/592/594 220-223 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 2J 3,5-dichloro-N-[[4-580/582/584 (3,4- dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-benzenesulfonamide 2K Methyl 2-[[[[4-(3,4- 570/572dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]amino]sulfonyl]-benzoate 2L 2-bromo-N-[[4-(3,4- 590/592/594 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 2M5-chloro-N-[[4-(3,4- 552/554/556 dichlorophenoxy)[1,4′- bipiperidin]-1′-yl]carbonyl]-2- thiophenesulfonamide 2N 4,5-dichloro-N-[[4- 586/588/590(3,4- dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-2-thiophenesulfonamide 2O 4-chloro-N-[[4-(3,4- 574/576/578dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-2,5- dimethyl-benzenesulfonamide 2P 2,5-dichloro-N-[[4- 586/588/590 (3,4-dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-3-thiophenesulfonamide 2Q N-[[4-(3,4- 596/598 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]-2- (trifluoromethoxy)- benzenesulfonamide2R 4-bromo-N-[[4-(3,4- 596/598/600 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]-2- thiophenesulfonamide 2S N-[[4-(3,4-596/598 dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-4-(trifluoromethoxy)- benzenesulfonamide 2T 5-chloro-N-[[4-(3,4-582/584/586 dichlorophenoxy) [1,4′- bipiperidin]-1′- yl]carbonyl]-2,4-difluoro- benzenesulfonamide 2U 4-chloro-N-[[4-(3,4- 582/584/586dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-2,5- difluoro-benzenesulfonamide 2V 3-chloro-N-[[4-(3,4- 578/580/582dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-5-fluoro- 2-methyl-benzenesulfonamide 2X N-[[4-(3,4- 540/542 (CD₃OD plus 1 drop NaOD)1.53(2H, dd), 1.98-2.24(7H, dichlorophenoxy)[1,4′- m), 2.63-2.74(2H, m),2.72(6H, s), 3.20-3.39(4H, m), bipiperidin]-1′- 4.43(2H, d),4.63-4.69(1H, m), 6.96(1H, dd), 7.05(2H, yl]carbonyl]-2,6- d), 7.14(1H,dd), 7.21(1H, d), 7.42(1H, d) dimethyl- benzenesulfonamide 2YN-[[4-(3,4- 555/557 (CD₃OD plus 1 drop NaOD) 1.27-1.42(2H, m), 1.70-1.86dichlorophenoxy)[1,4′- (4H, m), 1.96-2.05(2H, m), 2.41-2.54(3H, m),2.57- bipiperidin]-1′- 2.67(2H, m), 2.73(6H, s), 2.80-2.88(2H, m),4.35-4.47 yl]carbonyl]-2- (3H, m), 6.88(1H, dd), 7.08-7.14(2H, m),7.30-7.43(3H, (dimethylamino)- m), 7.98(1H, dd) benzenesulfonamide 2ZN-[[4-(3,4- 555/557 (DMSO) 1.15(3H, t), 1.20-1.28(2H, m), 1.53-1.63(2H,dichlorophenoxy)[1,4′- m), 1.65-1.72(2H, m), 1.88-1.96(2H, m), 2.37-2.47bipiperidin]-1′- (3H, m), 2.57-2.68(2H, m), 2.70-2.79(2H, m), 3.08(2H,yl]carbonyl]-4- dt), 3.94-4.01(2H, m), 4.39-4.47(1H, m), 6.38-6.43(ethylamino)- (1H, m), 6.53-6.58(2H, m), 6.97(1H, m), 7.25(1H, d),benzenesulfonamide 7.48-7.51(1H, m), 7.53-7.57(2H, m) 5B N-Benzoyl-4-(4-492/494 (CD₃OD) 1.57-1.73(m, 2H), 1.75-1.88(m, 2H), 1.90- 237-238chloro-2- 2.07(m, 4H), 2.19(s, 3H), 2.37-2.49(m, 1H), 2.50-2.61methylphenoxy)-[1,4′- (m, 2H), 2.73-2.91(m, 4H), 3.80-3.90(m, 2H), 4.36-bipiperidine]-1′- 4.45(m, 1H), 6.87-6.91(m, 1H), 7.07-7.13(m, 2H), 7.32-sulfonamide 7.46(m, 3H), 8.04(d, 2H); (plus 1 drop of 30% NaOD in D₂O)5C N-Benzoyl-4-[(3,4- 510/512 (CD₃OD) 8.00(2H, dt), 7.43-7.37(2H, m),7.36-7.29(3H, 193-196 dichlorophenyl)methyl]- m), 7.09(1H, dd), 3.81(2H,d), 2.94(2H, d), 2.74(2H, t), [1,4′-bipiperidine]- 2.53(2H, d), 2.35(1H,t), 2.18(2H, t), 1.89(3H, s), 1.67- 1′-sulfonamide 1.48(5H, m),1.33-1.21(2H, m) 5D N-benzoyl-4-(3,4- 526/528 (CD₃OD plus 1 drop NaOD)1.58-1.70(2H, m), 1.76-1.86 198-199 dichloro-2- (2H, m), 1.90-1.96(2H,m), 1.97-2.05 (2H, m), 2.31(3H, methylphenoxy)-[1,4′- s), 2.38-2.47(1H,m), 2.51-2.58(2H, m), 2.74-2.88(4H, bipiperidine]-1′- m), 3.81-3.87(2H,m), 4.40-4.47(1H, m), 6.91(1H, d), sulfonamide 7.27(1H, d),7.31-7.36(2H, m), 7.38-7.43(1H, m), 8.00- 8.03 (2H, m) 5EN-benzoyl-4-(2,4- 512/514 (CD₃OD plus 1 drop NaOD) 1.58-1.70(2H, m),1.79-1.88 233-235 dichlorophenoxy)- (2H, m); 1.90-2.04(4H, m),2.38-2.47(1H, m), 2.51- [1,4-bipiperidine]-1′- 2.58(2H, m),2.74-2.82(2H, m), 2.84-2.92(2H, m), 3.81- sulfonamide 3.87(2H, m),4.45-4.52(1H, m), 7.08(1H, d), 7.23(1H, dd), 7.31-7.36(2H, m),7.39-7.43(2H, m), 8.00-8.03 (2H, m) 6B trans N-[[4-[4-(3,4- 525/527(CD₃OD) 1.33(4H, d), 1.66-1.79(2H, m), 1.83-2.12(7H, dichlorophenoxy)-1-m), 2.25-2.37(1H, m), 2.50(2H, s), 2.64(3H, s), 2.78-piperidinyl]cyclohexyl] 2.89(2H, m), 4.32-4.40(1H, m), 6.87(1H, dd),7.08(1H, carbonyl]-2-methyl- d), 7.22(2H, d), 7.30-7.34(1H, m), 7.36(1H,d), 7.98(1H, d) benzenesulfonamide 6C trans N-[[4-[4-(3,4- 541/543(CD₃OD) 1.27-1.45(4H, m), 1.70-1.81(2H, m), 1.85- dichlorophenoxy)-1-2.19(7H, m), 2.24-2.39(1H, m), 2.45-2.58(2H, m), 2.80-piperidinyl]cyclohexyl] 2.91(2H, m), 3.89(3H, s), 4.33-4.44(1H, m),6.85-7.13 carbonyl]-2- (4H, m), 7.35-7.50(2H, m), 7.87-7.92(1H, m)methoxy-benzenesulfonamide 6D trans N-[[4-[4-(3,4- 539/541 (CD₃OD)1.34(4H, d), 1.64-1.80(2H, m), 1.85-2.14(7H, dichlorophenoxy)-1- m),2.25-2.37(1H, m), 2.45-2.57(2H, m), 2.73(6H, s), piperidinyl]cyclohexyl]2.80-2.90(2H, m), 4.32-4.41(1H, m), 6.85-6.92(1H, carbonyl]-2,6- m),7.00-7.21(4H, m), 7.38(1H, d) dimethyl-benzenesulfonamide 6E transN-[[4-[4-(3,4- 525/527/529 (CD₃OD plus 1 drop NaOD) 1.26-1.41(4H, m),1.72-1.82 dichlorophenoxy)-1- (2H, m), 1.88-2.13(7H, m), 2.28-2.37(1H,m), 2.40(3H, piperidinyl]cyclohexyl] s), 2.53(2H, s), 2.86(2H, s),4.40(1H, s), 6.90(1H, dd), carbonyl]-4-methyl- 7.11(1H, d), 7.27(2H, d),7.39(1H, d), 7.79(2H, d); benzenesulfonamide 6F trans N-[[4-[4-(3,4-511/513/515 (CD₃OD plus 1 drop NaOD) 6.78(1H, d), 6.99(1H, d), 7.27dichlorophenoxy)-1- (1H, d), 7.30-7.38(3H, m), 7.76-7.83(2H, m)piperidinyl]cyclohexyl] (of aromatic region only) carbonyl]-benzenesulfonamide 6G tarns N-[[4-[4-(3,4- 554/556/558 (CD₃OD plus 1drop NaOD) 1.27-1.46(4H, m), 1.71-1.85 dichlorophenoxy)-1- (2H, m),1.88-2.12(7H, m), 2.31-2.40(1H, m), 2.53(2H, piperidinyl]cyclohexyl] t),2.86(2H, d), 3.03(6H, s), 4.36-4.45(1H, m), 6.73(2H, carbonyl]-4- d),6.91(1H, dd), 7.11(1H, d), 7.40(1H, d), 7.74(2H, d) (dimethylamino)-benzenesulfonamide 8B N-(3-cyanobenzoyl)- 537/539 (DMSO) 1.55-1.80(4H,m), 1.92-2.18(6H, m), 2.63- 254-255 4-(3,4- 2.75(2H, m), 3.00-3.26(4H,m), 3.59-3.77(2H, m), 6.96- dichlorophenoxy)-[1,4- 7.11(1H, m),7.29-7.41(1H, m), 7.44-7.63(2H, m), bipiperidine]-1- 7.85(1H, d),8.21(2H, dt) sulfonamide 8C 4-(3,4- 530/532 (DMSO) 1.55-1.80(3H, m),1.92-2.18(6H, m), 2.63- 141-143 dichlorophenoxy)-N- 2.75(2H, m),3.00-3.26(4H, m), 3.59-3.77(2H, m) 3.59- (4-fluorobenzoyl)-[1,4′-3.78(1H, m), 6.89-7.24(3H, m), 7.33(1H, s), 7.53(1H, bipiperidine]-1′-d), 7.96(2H, dd) sulfonamide 8D 4-(3,4- 590/592 (DMSO) 1.46-2.20(10H,m), 2.62-2.80(6H, m), 3.24 244-246 dichlorophenoxy)-N-[3- (3H, s),3.66-3.76(2H, m), 7.04(1H, s), 7.35(1H, s), 7.54(methylsulfonyl)benzoyl]- (1H, d), 7.62(1H, t), 7.95(1H, d), 8.23(1H,dt), 8.42(1H, t) [1,4′-bipiperidine]- 1′-sulfonamide 8E 4-(4-chloro-2-570/572 (DMSO) 1.51-1.79(4H, m), 1.91-2.24(8H, m), 2.64- 235-236methylphenoxy)-N-[3- 2.75(3H, m), 3.20(3H, s), 3.66-3.75(2H, m),4.43-4.81 (methylsulfonyl)benzo (1H, m), 6.98-7.05(1H, m), 7.19(1H, dd),7.24(1H, d), yl]-[1,4-bipiperidine]- 7.62(1H, t), 7.94(1H, d), 8.23(1H,dt), 8.42(1H, t) 1′-sulfonamide 8F N-(2-chlorobenzoyl)- 546/548/550(DMSO) 1.44-1.73(4H, m), 1.86-2.17(6H, m), 2.63- 187-1884-(3,4-dichlorophenoxy)- 2.77(2H, m), 3.03-3.16(4H, m), 3.64-3.72(2H,m), 7.03 [1,4-bipiperidine]-1′- (1H, d), 7.32-7.42(3H, m), 7.54(1H, d),7.92(2H, dt) sulfonamide 8G N-(4-chlorobenzoyl)- 546/548/550 (DMSO)0.92-2.22(11H, m), 2.57-2.78(6H, m), 3.63- 156-1574-(3,4-dichlorophenoxy)- 3.77(1H, m), 7.03(1H, d), 7.31-7.41(3H, m),7.54(1H, d), [1,4′-bipiperidine]-1′- 7.92(2H, dd) sulfonamide 8HN-(4-chlorobenzoyl)- 526/528 (DMSO) 1.02-1.61(4H, m), 1.63-2.03(3H, m),2.13- 138-139 4-(4-chloro-2- 2.19(2H, m), 2.52(3H, s), 2.56-2.69(3H, m),2.97-3.14 methylphenoxy)-[1,4′- (4H, m), 3.52-3.78(2H, m), 7.00(1H, d),7.16(1H, dd), bipiperidine]-1′- 7.22(1H, d), 7.32-7.39(2H, m), 7.91(2H,dt) sulfonamide 9B 4-(3,4- 542/544 (DMSO) 0.95-1.31(3H, m),1.31-1.96(6H, m), 2.24(3H, 202-203 dichlorophenoxy)-N- s), 2.57-2.75(7H,m), 3.55-3.73(2H, m), 6.95-7.05(2H, (2-methoxybenzoyl)- m), 7.13(1H, d),7.26(1H, d), 7.47(3H, dd) [1,4′-bipiperidine]-1′- sulfonamide 9C 4-(3,4-542/544 (DMSO) 1.40-2.19(6H, m), 2.70-2.89(5H, m), 2.95- 142-143dichlorophenoxy)-N- 3.13(2H, m), 3.68-3.79(4H, m), 3.87(3H, s),4.43-4.66 (4-methoxybenzoyl)- (1H, m), 6.95(2H, d), 7.01(1H, dd),7.30(1H, d), 7.52(1H, [1,4′-bipiperidine]-1′- d), 7.90(2H, dd)sulfonamide 10B N-[[4-(3,4- 526/528 (DMSO) 1.16(2H, qd), 1.50-1.61(4H,m), 1.87-1.94(2H, dichlorophenoxy)[1,4′- m), 2.28-2.46(5H, m),2.69-2.75(2H, m), 4.18-4.27 bipiperidin]-1′- (2H, m), 4.39(1H, septet),6.97(1H, dd), 7.11(2H, t), 7.20 yl]carbonyl]-2- (1H, td), 7.25(1H, d),7.48(1H, d), 7.74(1H, d) methylbenzenesulfona- mide sodium salt 10CN-[[4-(3,4- 512/514 (DMSO) 1.16(2H, qd), 1.49-1.62(4H, m), 1.87-1.94(2H,dichlorophenoxy)[1,4′- m), 2.27-2.46(5H, m), 2.69-2.75(2H, m), 4.17-4.26bipiperidin]-1′- (2H, m), 4.39(1H, septet), 6.97(1H, dd), 7.25(1H, d),7.29- yl]carbonyl]- 7.33(3H, m), 7.48(1H, d), 7.69-7.72(2H, m)benzenesulfonamide sodium salt 10D N-[[4-(4-chloro-2- 506/508 (DMSO)1.10-1.21(2H, m), 1.54-1.65(4H, m), 1.83- methylphenoxy)[1,4′- 1.91(2H,m), 2.28(3H, s), 2.12(3H, d), 2.30-2.46(5H, m), bipiperidin]-1′-2.65-2.72(2H, m), 4.20(2H, d), 4.32-4.39(1H, m), 6.97 yl]carbonyl]-4-(1H, d), 7.10(2H, d), 7.13(1H, dd), 7.19(1H, dd), 7.58 (2H,methyl-benzenesulfonamide d) sodium salt 16B 4-(3,4- 604/606/608 274-276dichlorophenoxy)-N- recrystallised [[4-(1,1- from DMSO-dimethylethyl)phenyl] methanol. sulfonyl]-[1,4′- bipiperidine]-1′-sulfonamide

The preparations of certain intermediates are now presented.

Method A

[1,4′]Bipiperidinyl-4-ol

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200ml) with acetic acid (4 ml) at RT for 30 minutes. Sodiumtriacetoxyborohydride (23 g) was then added and the mixture stirred atRT overnight. The mixture was evaporated to dryness and the residuetaken into water, extracted with diethyl ether (3×200 ml), the aqueouswas basified to pH 9-10 and extracted with dichloromethane (3×200 ml).The dichloromethane extracts were combined, dried (MgSO₄) and evaporatedto leave an oil (19 g). The oil was dissolved in methanol (300 ml) andtreated with concentrated hydrochloric acid (5 ml). The mixture wasstirred overnight and then evaporated to dryness to leave the titlecompound as the hydrochloride salt (15 g).

¹H NMR (400 MHz, DMSO-D6) δ 1.6-2.4 (m, 9H), 2.8-3.5 (m, 8H), 3.62 (m,1H), 3.95 (s, 1H), 9.29 and 9.059 (bs, 2H), 10.9 and 11.09 (bs, 1H).

Method B

4-(3,4-Dichlorophenoxy)piperidine

Step a: tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate

Diethyl azodicarboxylate (41.0 ml) was added to a solution oftriphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) intetrahydrofuran (400 ml) was added dropwise over 30 min. The solutionwas stirred at room temperature for 16 hours and concentrated to a smallvolume. Purification by chromatography (ethyl acetate:iso-hexane 95:5)gave the sub-title compound as an oil (61.3 g).

MS: APCI(+ve): 246/248 (M-BOC+2H)

Step b: 4-(3,4-Dichlorophenoxy)piperidine

The product from Step a was dissolved in dichloromethane (600 ml) andtrifluoroacetic acid (300 ml) was added. After 24 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the sub-title product as a solid (36.6 g). The freebase was liberated by addition of aqueous NaOH (2M) and extraction withethyl acetate followed by evaporation of solvent to give the titlecompound as a gum (25 g).

¹H NMR: δ (CDCl₃) 1.77 (1H, br s), 2.05-2.26 (4H, m), 3.20-3.49 (4H, m),4.61 (1H, s), 6.69-7.52 (3H, m).

Method C

4-(3,4-Dichlorophenoxy)-[1,4′]bipiperidine

Step a: 4-(3,4-Dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g)followed by NaBH(OAc)₃ (1.81 g) and acetic acid (0.37 g). After 18 hoursat room temperature aqueous NaOH (1M) solution and diethyl ether wereadded. The product was extracted with diethyl ether, the combinedorganic extracts dried with MgSO₄ and concentrated. Purification bychromatography (dichloromethane methanol 92:8) gave the sub-titleproduct (1.97 g; MS: APCI(+ve): 429/431 (M+H)).

Step b: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine

The product of Step a was dissolved in dichloromethane (30 ml) andtrifluoroacetic acid (15 ml) was added. After 4 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the trifluoroacetate salt of the sub-titled productas a solid (1.15 g). The free base was liberated by addition of aqueousNaOH (2M) and extraction with ethyl acetate followed by evaporation ofsolvent to give the sub-title compound as a solid (0.68 g).

¹H NMR: δ(CDCl₃) 1.38-1.51 (2H, m), 1.74-2.02 (6H, m), 2.38-2.50 (3H,m), 2.56-2.61 (2H, m), 2.79-2.86 (2H, m), 3.14-3.18 (2H, m), 4.22-4.28(1H, m), 6.73-7.32 (3H, m).

The following intermediates were prepared in a similar manner to MethodC:

MS: (M + H) 4-(4-chloro-2-methylphenoxy)-1,4′-bipiperidine 309/3114-(2-chloro-4-fluorophenoxy)-1,4′-bipiperidine 313/3154-(3,4-diflorophenoxy)-1,4′-bipiperidine 2974-(2,4-dichlorophenoxy)-1,4′-bipiperidine 329/3314-(2,4-dichloro-3-methylphenoxy)-1,4′-bipiperidine 343/3454-(3,4-dichloro-2-methylphenoxy)-1,4′-bipiperidine 343/345 ¹4-[(3,4-Dichlorophenyl)methyl]-1,4′-bipiperidine 327/329 ²2-([1,4′-bipiperidin]-4-yloxy)-5-chloro-pyridine ³ ¹ for startingmaterial see DE19837386 ² for starting material see WO 00/12478 ³ ¹H NMR(399.978 MHz, CDCl₃): δ 1.44(2H, qd), 1.74-1.86(5H, m), 2.01-2.07(2H,m), 2.38-2.42(1H, m), 2.44-2.50(2H, m), 2.60(2H, td), 2.82-2.87(2H, m),3.15(2H, d), 4.98(1H, septet), 6.66(1H, d), 7.50(1H, dd), 8.06(1H, d).

Method D

4-(3-Chloro-4-fluoro-phenoxy)-piperidine

DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g),3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylicacid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture wasstirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixturestirred at RT overnight. The mixture was then evaporated to dryness andtriethylamine (5 ml) was added. The mixture was evaporated and theresidue was dissolved in methanol (10 ml), placed onto a SCX cartridge(Varian, 10 g, SCX cartridge available from International SorbentTechnology Isolute® Flash SCX-2) and eluted: first with methanol thenwith 10% NH₃ in methanol. The basic fractions were combined andevaporated to give the product as an oil (0.6 g).

¹H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.46 (2H, m), 1.83-1.91 (2H, m),2.53-2.59 (2H, m), 2.87-2.96 (2H, m), 3.22-3.39 (1H, m), 4.39 (1H,septet), 6.92-6.98 (1H, m), 7.17-7.20 (1H, m), 7.30 (1H, t).

The following intermediates were prepared in similar manner to Method D:

MS: (M + H) 4-(4-chloro-2-methyl-phenoxy)-piperidine 226/2284-(4-chloro-3-fluoro-phenoxy)-piperidine 230/2324-(4-chloro-2-methoxy-phenoxy)-piperidine 242/2444-(4-fluoro-2-methoxy-phenoxy)-piperidine 2264-(4-methoxy-phenoxy)-piperidine 208 4-p-tolyloxy-piperidine 1924-(4-chloro-3-methyl-phenoxy)-piperidine 226/2284-(4-chloro-phenoxy)-piperidine 212/214 4-(4-fluoro-phenoxy)-piperidine196 4-(2,4-dichloro-phenoxy)-piperidine 246/2484-(2-chloro-4-fluoro-phenoxy)-piperidine 230/2324-(2,4-difluoro-phenoxy)-piperidine 2144-(4-chloro-2-fluoro-phenoxy)-piperidine 230/2324-(4-fluoro-2-methyl-phenoxy)-piperidine 2104-(4-chloro-2,6-dimethyl-phenoxy)-piperidine 240/2424-(2,3-dichloro-phenoxy)-piperidine 246/2484-(2,5-dichloro-phenoxy)-piperidine 246/2484-(2-chloro-4-methyl-phenoxy)-piperidine 226/2284-(2-chloro-5-methyl-phenoxy)-piperidine 226/2281-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-ethanone 2344-(2-chloro-6-methyl-phenoxy)-piperidine 226/2284-(4-chloro-2-ethyl-phenoxy)-piperidine 240/2427-(piperidin-4-yloxy)-quinoline 229 4-(2-tert-butyl-phenoxy)-piperidine234 4-(indan-5-yloxy)-piperidine 2184-(4-chloro-2-cyclohexyl-phenoxy)-piperidine 294/2965-chloro-2-(piperidin-4-yloxy)-benzamide 255/2574-(4-chloro-2-isoxazol-5-yl-phenoxy)-piperidine 279/2814-(5-chloro-2-methyl-phenoxy)-piperidine 226/228 4-phenoxy-piperidine178 4-(2,4-dichloro-6-methyl-phenoxy)-piperidine 260/2624-(3-chloro-4-methyl-phenoxy)-piperidine 226/2285-chloro-2-(piperidin-4-yloxy)-benzonitrile 237/2394-(2,4-dichloro-3-methyl-phenoxy)-piperidine 260/2624-(2-ethyl-4-fluoro-phenoxy)-piperidine 2244-(4-methanesulfonyl-phenoxy)-piperidine 2974-(3,4-dichloro-2-methylphenoxy)-piperidine 260/262

Method E

4-(3,4-Dichlorophenoxy)-4′-methyl-1,4′-bipiperidine dihydrochloride

a) 1,1-Dimethylethyl4′-cyano-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′carboxylate

4-(3,4-Dichlorophenoxypiperidine) (Method B step b; 500 mg) wasdissolved in dichloroethane (2 ml) with 1-Boc-4-piperidone (446 mg).Titanium teraisopropoxide (0.85 ml) was added and the mixture wasstirred overnight. The solvent was evaporated and toluene (5 ml) wasadded followed by diethylaluminium cyanide (3 ml of 1M solution intoluene). The mixture was stirred for 3 h, then ethyl acetate was added(5 ml) followed by water (0.5 ml) and the mixture was stirred for afurther 2 h. The mixture was filtered through a GF filter paper, andevaporated to give the subtitle compound (912 mg; MS

[M+H]+ (APCI+) 454/456). ¹H NMR (399.98 MHz, CD₃OD) δ 1.36 (s, 9H),1.57-1.77 (m, 4H), 1.90-1.99 (m, 2H), 2.04-2.12 (m, 2H), 2.44-2.52 (m,2H), 2.77-2.87 (m, 2H), 3.02-3.13 (m, 2H), 3.82 (dt, 2H), 4.31-4.40 (m,1H), 6.81 (dd, 1H), 7.02 (d, 1H), 7.29 (d, 1H).

b) 1,1-Dimethylethyl4-(3,4-dichlorophenoxy)-4′-methyl-[1,4′-bipiperidine]-1′-carboxylate

1,1-Dimethylethyl4′-cyano-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxylate (100mg) was dissolved in THF (6 ml). Methyl magnesium bromide (3M in ether,220 μl) was added and the mixture was stirred at RT for 2 h. Furthermethyl magnesium bromide (220 μl) was added and the solution was stirredfor a further 60 h. Potassium carbonate solution (saturated aqueous) wasadded and the mixture was extracted with DCM. The organic phase wasdried, filtered and evaporated to give the subtitle compound (100 mg; MS[M+H]⁺ (APCI+) 443/445).

¹H NMR (299.945 MHz, CD₃OD) δ 1.01 (s, 3H), 1.47 (s, 9H), 1.69-1.84 (m,4H), 1.97-2.08 (m, 2H), 2.42-2.52 (m, 2H), 2.81-2.92 (m, 2H), 3.36-3.42(m, 2H), 3.45-3.57 (m, 2H), 3.62-3.89 (m, 2H), 4.32-4.41 (m, 1H), 6.89(dd, 1H), 7.10 (d, 1H), 7.38 (d, 1H).

c) 4-(3,4-dichlorophenoxy)-4′-methyl-1,4′-bipiperidine dihydrochloride

1,1-Dimethylethyl4-(3,4-dichlorophenoxy)-4′-methyl-[1,4′-bipiperidine]-1′-carboxylate(100 mg) was dissolved in ethanol (5 ml). Hydrogen chloride (2 ml of 4Min dioxan) was added and the solution was stirred overnight. Furtherhydrogen chloride solution (2 ml) was added and the mixture was stirredfor a further 2 h. The solvents were evaporated to give the titlecompound (95 mg; MS [M+H]⁺ (APCI+) 343/345).

Method F

trans Sodium4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

a) Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

4-(3,4-Dichlorophenoxy)piperidine (Method B, 1.44 g), ethyl4-oxocyclohexanecarboxylate (1.0 g) and acetic acid (0.34 ml) werecombined in THF 10 ml and the solution was cooled in ice. Sodiumtriacetoxy borohydride (1.45 g) was added and the mixture was stirredovernight and allowed to come to ambient temperature. The reactionmixture was poured onto a stirred saturated aq solution of sodiumbicarbonate. The mixture was extracted with ethyl acetate thrice, theorganic phases were washed with brine, dried, filtered and evaporated.The residue was purified on an SCX cartridge (International SorbentTechnology Isolute® Flash SCX-2), washed with methanol and then producteluted with 0.7M ammonia in methanol. Further purification bychromatography (silica, 90:9:1 DCM:methanol:triethylamine) gave thesubtitle compound (1.59 g; MS [M+H]⁺ (APCI+) 400/402) as a mixture ofcis/trans isomers.

¹H NMR (399.98 MHz, CD₃OD) δ 1.23 (t), 1.25 (t), 1.28-1.59 (m),1.70-1.81 (m), 1.96-2.07 (m), 2.17-2.27 (m), 2.32-2.40 (m), 2.45-2.56(m), 2.581-2.61 (m), 2.80-2.89 (m), 3.30 (quintet), 4.10 (q), 4.14 (q),4.34-4.40 (m), 6.88 (dd), 6.88 (dd), 7.09 (d), 7.09 (d), 7.37 (d), 7.37(d).

b) trans Sodium4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

Ethyl 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate(0.97 g) was added to a solution of sodium ethoxide in ethanol (preparedfrom sodium (1.28 g) and ethanol (100 ml)) the solution was heated toreflux overnight. Acetic acid was added and the solvent was evaporated.Ethyl acetate, water and sodium hydroxide were added to the residue andan insoluble white solid formed which was collected by filtration anddried in vacuo to give the sub-titled compound (469 mg; MS [M−Na]⁻(APCI−) 370/372) containing sodium acetate.

¹H NMR (399.98 MHz, CD₃OD) δ 1.27-1.38 (m, 2H), 1.46 (q, 2H), 1.72-1.81(m, 2H), 1.95-2.09 (m, 7H), 2.40 (t, 1H), 2.55 (td, 2H), 2.84-2.91 (m,2H), 4.39 (septet, 1H), 6.89 (dd, 1H), 7.10 (d, 1H), 7.37 (d, 1H).

Method G

4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide

4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (5 g, 0.0152 mol) andsulfamide (1.45 g, 0.0152 mol) were stirred together in dioxan (150 ml)at reflux for 24 hours. The resulting mixture was cooled to ambienttemperature, evaporated to dryness and the residue was triturated withether to give the title compound as a tan solid (5 g; MS APCI 409/411(M+H)).

¹H NMR (399.98 MHz, DMSO) δ 1.38-2.03 (m, 6H), 2.25-2.45 (m, 6H),2.66-2.84 (m, 3H), 3.41-3.53 (m, 2H), 4.35-4.47 (m, 1H), 6.31-6.45 (m,2H), 6.91-7.03 (m, 1H), 7.18-7.31 (m, 1H), 7.43-7.55 (m, 1H).

Method H

4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide.

4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (2.0 g) was dissolved inglacial acetic acid (0.608 ml), the solution was diluted with water (6ml) and added with stirring to a solution of sodium cyanate (0.395 g) inwarm water (3 ml). The reaction was allowed to stand for 30 mins. 2MSodium hydroxide solution was added until the solution was alkaline. Theresulting precipitate was collected and washed with water followed bydichloromethane and then dried to leave the sub-title compound (1.3 g;ES+ 372/374).

¹H NMR (399.98 MHz, DMSO) δ 1.20-1.31 (m, 2H), 1.51-1.61 (m, 2H),1.62-1.69 (m, 2H), 1.88-1.95 (m, 2H), 2.32-2.44 (m, 3H), 2.55-2.64 (m,2H), 2.70-2.77 (m, 2H), 3.92-3.99 (m, 2H), 4.37-4.44 (m, 1H), 5.86 (s,2H), 6.95-6.99 (m, 1H), 7.24-7.25 (m, 1H), 7.49 (d, 1H).

Method I

2,4-Dichloro-3-fluorophenol

a) N,N-Diethyl-4-chloro-3-fluorophenyl carbamate

A solution of 4-chloro-3-fluorophenol (26.9 g) and diethylcarbamoylchloride (25 g) in pyridine (100 ml) was heated to 100° C. for 12 h andthen allowed to cool. Water (100 ml) was added and the product wasextracted with diethylether/pentane (1:1) (50 ml×2). The combinedorganic extracts were washed with HCl (2M, 70 ml), NaOH (2M, 75 ml) anddried (MgSO₄), filtered and evaporated to give the subtitle compound asan oil (37.7 g)

¹H NMR δ (CDCl₃) 1.18-1.26 (6H, m), 3.35-3.44 (4H, m), 6.90 (1H, ddd),6.99-7.02 (1H, m), 7.35 (1H, t)

b) N,N-Diethyl-2,4-dichloro-3-fluorophenyl carbamate

To a solution of N,N-diethyl-4-chloro-3-fluorophenyl carbamate (15 g) inTHF (100 ml) and TMEDA (9.7 ml) at −90° C. was added secBuLi (1.3M, 49.5ml) whilst maintaining the temperature between −80° C. and −90° C. Themixture was stirred at −80° C. for 2 h. 1,1,1,2,2,2-Hexachloroethane(17.39 g) as a solution in THF (50 ml) was added. During this period thereaction was allowed to warm to 0° C. Water (50 ml) was added and theproduct was extracted with pentane. The combined organic extracts weredried (MgSO₄) and filtered. Evaporation of solvent and purification byHPLC (Waters XTerra® column)(gradient (25% MeCN/NH3(aq) (0.1%) to 95%MeCN//NH3(aq) (0.1%)) gave the subtitle compound as an oil (9.3 g).

¹H NMR δ (CDCl₃) 1.19-1.32 (6h, m), 3.36-3.51 (4H, m), 7.03 (1H, dq),7.26-7.33 (1H, m)

2,4-Dichloro-3-fluorophenol

N,N-Diethyl-2,4-dichloro-3-fluorophenyl carbamate (8.14 g) was dissolvedin THF (17 ml). A solution of lithium aluminium hydride (33 ml of 1M inTHF) was added dropwise and the resulting solution was stirredovernight. Ethanol was added followed by hydrochloric acid (2M, 17 ml).The resulting suspension was filtered and the solid was washed withether. The phases were separated, the aqueous phase was extracted thricewith ether and the combined organic phases were dried (MgSO₄), filtered-and evaporated to give the title compound (3.4 g).

¹H NMR δ (CD₃OD) 6.65 (1H, dd), 7.11 (1H, t)

Method J

2,6-Dimethyl-benzenesulfonamide

To a solution of 2,6-dimethyl-benzenethiol (2 ml) in water (20 ml),chlorine gas was introduced over 15 minutes resulting in precipitationof an orange solid. The reaction was left to stir in a stoppered flaskfor a further 60 minutes. An excess of ammonia solution (0.88 sg) wasadded and the mixture was left to stir for 12 h. The reaction wasevaporated to remove ammonia and then filtered. The solid was washedwith water followed by iso-hexane to give the title compound.

MS [M−H]⁻ (ES−) 184

¹H NMR δ (DMSO) 2.59 (6H, s), 7.18 (2H, d), 7.27 (2H, s), 7.30 (1H, t)

Method K

trans 4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylicacid

a) trans Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

Ethyl 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate(method F, step a, 0.97 g) was added to a solution of sodium ethoxideprepared from sodium (1.28 g) and ethanol (100 ml). The resultantsolution was heated under reflux for 18 h. Acetic acid (0.1 ml) wasadded and the solvent was evaporated. Ethyl acetate, water and sodiumhydroxide were added to the residue and separated. The aqueous phase wasextracted twice with ethyl acetate-methanol mixtures and the combinedorganic phases were washed with brine, dried (MgSO₄), filtered andevaporated to give the subtitle compound as an oil.

MS [M+H]⁺ (APCI+) 400/402 ¹H NMR of major isomer (ca 3.5:1 ratio) δ(acetone) 1.20 (3H, t), 1.27-1.46 (4H, m), 1.57 1.71 (3H, m), 1.84-1.90(2H, m), 1.95-2.02 (4H, m), 2.15-2.23 (1H, m), 2.27-2.41 (2H, m), 2.46(2H, ddd), 4.06 (2H, q), 4.40 (1H, septet), 6.95 (1H, dd), 7.15 (1H, d),7.43 (1H, d)

b) trans 4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylicacid

trans Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (0.8 g)was dissolved in t-BuOH (180 ml) at 38° C. To this was added Candiarugosa lipase powder (3 g). This was stirred for 30 minutes then water(20 ml) was added over 4 h. The mixture was then stirred for 48 h andfiltered. The enzyme was washed with 9:1 t-BuOH-water (2×20 ml) and thefiltrate was evaporated. Ethyl acetate was added to the residue and thendecanted. The resultant solid was dissolved in methanol/DMSO and waspurified by HPLC (Waters XTerra® column with at-column dilution ofsample) (gradient (5% MeCN/NH3(aq) (0.2%) to 40% MeCN//NH3(aq) (0.2%)]gave the title compound (0.44 g) as a white solid.

m.pt. 167-168° C. MS [M+H]⁺ (ES+) 372/374 ¹H NMR δ_((DMSO))1.19-1.36(4H, m), 1.50-1.59 (2H, m), 1.78 (2H, d), 1.87-1.96 (4H, m), 2.09 (1H,td), 2.24-2.32 (1H, m), 2.38 (2H, td), 2.72 (2H, dt), 4.39 (1H, septet),6.97 (1H, dd), 7.24 (1H, d), 7.49 (1H, d)

Method L

1,1-Dimethylethyl[4-(3,4-dichlorophenoxy)-1,4′-bipiperidin-1′-yl]sulfonylcarbamate

tert-Butanol (0.48 ml) in dichloromethane (2 ml) was added to a solutionof chlorosulfonylisocyanate (0.43 ml) in dichloromethane (5 ml) stirringat 0° C. The resulting solution was then added to a solution of4-(3,4-dichlorophenoxy)-1,4′-bipiperidine (1.6 g) and triethylamine(0.77 ml) in dichloromethane (20 ml) at 0° C. After stirring at 0° C.for 2 h, the reaction mixture was washed with 0.1M hydrochloric acid (30ml), dried (MgSO₄) and evaporated. The residue was triturated withdiethylether (20 ml) to give the title compound as a white solid. (1.9g)

¹H NMR δ_((DMSO))1.44 (9H, s), 1.64-1.77 (2H, m), 1.94-2.08 (2H, m),2.15-2.27 (4H, m), 2.86 (2H, t), 3.03-3.18 (2H, m), 3.28-3.53 (3H, m),3.76 (2H, d), 4.59-4.81 (1H, m), 6.99-7.11 (1H, m), 7.33-7.39 (1H, m),7.52-7.58 (1H, m)

EXAMPLE 17 Pharmacological Analysis: Calcium Flux [Ca²⁺]_(i) Assay

Human Eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended (5×10⁶ ml⁻¹) and loaded with 5μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassiumsolution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM, glucose 5.5 mM, Na₂CO₃ 8.5 mM,KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4) for one hour atroom temperature. After loading, cells were centrifuged at 200 g for 5min and resuspended in LKS at 2.5×10⁶ ml⁻¹. The cells were thentransferred to 96 well FLIPr plates (Poly-D-Lysine plates from BectonDickinson pre-incubated with 5 μM fibronectin for two hours) at 25μl/well. The plate was centrifuged at 200 g for 5 min and the cells werewashed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to afinal concentration of 0.1%(v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of eotaxin and the transient increasein fluo-3 fluorescence (1_(Ex)=490 nm and 1_(Em)=520 nm) monitored usinga FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, U.S.A.).

Compounds of the Examples were found to be antagonists if the increasein fluorescence induced by eotaxin (a selective CCR3 agonist) wasinhibited in a concentration dependent manner. The concentration ofantagonist required to inhibit the fluorescence by 50% can be used todetermine the IC₅₀ for the antagonist at the CCR3 receptor.

Human Eosinophil Chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended at 10×10⁶ ml⁻¹ in RPMIcontaining 200 IU/ml penicillin, 200 μg/ml streptomycin sulfate andsupplemented with 10% HIFCS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μlof either vehicle or compound (100× required final concentration in 10%DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loadedby adding 28 μl of a concentration of eotaxin 0.1 to 100 nM (a selectiveCCR3 agonist over this concentration range) containing a concentrationof a compound according to the Examples or solvent to the lower wells ofthe chemotaxis plate. The filter was then placed over the wells and 25μl of eosinophil suspension were added to the top of the filter. Theplate was incubated for 1 hr at 37° C. in a humidified incubator with a95% air/5% CO₂ atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefullyaspirated from above the filter and discarded. The filter was washedonce with phosphate buffered saline (PBS) containing 5 mM EDTA to removeany adherent cells. Cells that had migrated through the filter werepelleted by centrifugation (300×g for 5 mins at room temperature) andthe filter removed and the supernatant transferred to each well of a96-well plate (Costar). The pelleted cells were lysed by the addition of28 μl of PBS containing 0.5% Triton ×100 followed by two cycles offreeze/thawing. The cell lysate was then added to the supernatant. Thenumber of eosinophils migrating was quantified according to the methodof Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuringeosinophil peroxidase activity in the supernatant.

Compounds of the Examples were found to be antagonists of eotaxinmediated human eosinophil chemotaxis if the concentration response toeotaxin was shifted to the right of the control curve. Measuring theconcentration of eotaxin required to give 50% chemotaxis in the presenceor absence of compounds enables the apparent affinity of the compoundsat CCR3 to be calculated.

1. A compound of formula (I):

wherein: T is C(O) or S(O)₂; W is C(O) or S(O)₂; X is CH₂, O or NH; Y isN; R¹ is optionally substituted aryl or optionally substitutedheterocyclyl; R² is hydrogen or C₁₋₆ alkyl; R³ is hydrogen; R⁴ is alkyl,optionally substituted aryl, optionally substituted aralkyl oroptionally substituted heterocyclyl; R⁵ is hydrogen or C₁₋₆ alkyl;wherein the foregoing aryl and heterocyclyl moieties are optionallysubstituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)_(p)R²⁵,OC(O)NR⁶R⁷, NR⁸R⁹, NR¹⁰C(O)R¹¹, NR¹²C(O)NR¹³R¹⁴, S(O)₂NR¹⁵R¹⁶,NR¹⁷S(O)₂R¹⁸, C(O)NR¹⁹R²⁰, C(O)R²¹, CO₂R²², NR²³CO₂R²⁴, C₁₋₆ alkyl, CF₃,C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, OCF₃, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆alkylthio, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itselfoptionally substituted by C₁₋₄ alkyl or oxo), methylenedioxy,difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy, phenylthio,phenyl(C₁₋₄)alkoxy, heteroaryl, heteroaryl(C₁₋₄)alkyl, heteroaryloxy orheteroaryl(C₁₋₄)alkoxy; wherein any of the immediately foregoing phenyland heteroaryl moieties are optionally substituted with halogen,hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; p and q are,independently, 0, 1 or 2; R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²², and R²³ are, independently, hydrogen, C₁₋₆alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl,C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃)or heterocyclyl (itself optionally substituted by halogen, hydroxy,nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃or OCF₃); alternatively NR⁶R⁷, NR⁸R⁹, NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁹R²⁰ orN(C₁₋₄ alkyl)₂ may, independently, form a 4-7 membered heterocyclicring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or1,4-piperazine, the latter optionally substituted by C₁₋₄alkyl on thedistal nitrogen; R²⁵, R¹⁸ and R²⁴ are, independently, C₁₋₆ alkyl(optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkylgroups may join to form a ring as described for R⁶ and R⁷ above),S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁶ andR⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R⁶ and R⁷ above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) orheterocyclyl (itself optionally substituted by halogen, hydroxy, nitro,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups may join toform a ring as described for R⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkylgroups may join to form a ring as described for R⁶ and R⁷ above), cyano,C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁶ andR⁷ above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃); or an N-oxide thereof; or apharmaceutically acceptable salt thereof.
 2. A compound as claimed inclaim 1 wherein X is O.
 3. A compound as claimed in claim 1 wherein R¹is phenyl substituted with one or more of fluorine, chlorine, C₁₋₄ alkylor C₁₋₄ alkoxy.
 4. A compound as claimed in claim 1 wherein one of T andW is C(O) and the other is S(O)₂.
 5. A compound as claimed in claim 1wherein T is C(O).
 6. A compound as claimed in claim 1 wherein W isS(O)₂.
 7. A compound as claimed in claim 1 wherein R² is hydrogen ormethyl.
 8. A compound as claimed in claim 1 wherein R⁴ is substitutedphenyl, the substituents being chosen from those provided in claim
 1. 9.A compound as claimed in claim 1 which is:N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;4-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;2-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;4-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;2-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;2-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;4-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;2-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;4-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;2-Chloro-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-3-trifluoromethylbenzenesulfonamide;3-Cyano-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenemethanesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-methanesulfonamide;N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;4-Chloro-N-[[4-(4-chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-[(3,4-Dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;4-Chloro-N-[[4-[(3,4-dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-[(3,4-Dichlorophenyl)amino]-[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;3-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;3,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;3-Cyano-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethoxybenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3,4-dimethoxy-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(3,3-dimethyl-2-oxo-1azetidinyl)-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-hydroxy-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(trifluoromethyl)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoicacid, methyl ester;2-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[5-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-1,3,4thiadiazol-2-yl]-acetamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-(dimethylamino)-1naphthalenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-naphthalenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-dimethyl-5thiazolesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(1-piperidinyl)-3pyridinesulfonamide;5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;5-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]tetrahydro-3thiophenesulfonamide; 1,1-dioxide4,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethylbenzenesulfonamide;4-n-Butyl-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;2,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3thiophenesulfonamide;4-n-Butoxy-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1-methyl-1H-imidazole-4sulfonamide;5-Amino-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1,3,4-thiadiazole-2sulfonamide;4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(4-morpholinyl)-3pyridinesulfonamide;6-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-pyridinesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(1,1-dimethylethyl)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-methyl-2-pyridinesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluorobenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(trifluoromethoxy)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluorobenzenesulfonamide;5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluorobenzenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluorobenzenesulfonamide;3-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methylbenzenesulfonamide;N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;2-chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;2-chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;2-chloro-N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;2-chloro-N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methoxy-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(dimethylamino)-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methoxy-benzenesulfonamide;4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;3,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;Methyl2-[[[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoate;2-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;4,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;4-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethyl-benzenesulfonamide;2,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-thiophenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluoro-benzenesulfonamide;4-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,6-dimethyl-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide;4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(3-cyanobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-benzoyl-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-benzoyl-4-(2,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(cyclohexylcarbonyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-methyl-1-oxopropyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-phenylacetyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide;4-(3,4-Dichlorophenoxy)-N-(2-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-(4-chlorobenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-benzoyl-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide;[4-(3,4-dichlorophenoxy)-N-(phenylsulfonyl)-1,4′-bipiperidine]-1′-sulfonamide.